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Dysregulated mitochondrial and chloroplast bioenergetics from a translational medical perspective (Review)

  • Authors:
    • George B. Stefano
    • Richard M. Kream
  • View Affiliations

  • Published online on: January 28, 2016     https://doi.org/10.3892/ijmm.2016.2471
  • Pages: 547-555
  • Copyright: © Stefano et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mitochondria and chloroplasts represent endosymbiotic models of complex organelle development, driven by intense evolutionary pressure to provide exponentially enhanced ATP-dependent energy production functionally linked to cellular respiration and photosynthesis. Within the realm of translational medicine, it has become compellingly evident that mitochondrial dysfunction, resulting in compromised cellular bioenergetics, represents a key causative factor in the etiology and persistence of major diseases afflicting human populations. As a pathophysiological consequence of enhanced oxygen utilization that is functionally uncoupled from the oxidative phosphorylation of ADP, significant levels of reactive oxygen species (ROS) may be generated within mitochondria and chloroplasts, which may effectively compromise cellular energy production following prolonged stress/inflammatory conditions. Empirically determined homologies in biochemical pathways, and their respective encoding gene sequences between chloroplasts and mitochondria, suggest common origins via entrapped primordial bacterial ancestors. From evolutionary and developmental perspectives, the elucidation of multiple biochemical and molecular relationships responsible for errorless bioenergetics within mitochondrial and plastid complexes will most certainly enhance the depth of translational approaches to ameliorate or even prevent the destructive effects of multiple disease states. The selective choice of discussion points contained within the present review is designed to provide theoretical bases and translational insights into the pathophysiology of human diseases from a perspective of dysregulated mitochondrial bioenergetics with special reference to chloroplast biology.

1. Introduction

Mitochondria and chloroplasts represent endosymbiotic models of complex organelle development driven by the evolutionary modification of permanently enslaved primordial bacteria, to provide exponentially enhanced ATP-dependent energy production functionally linked to cellular respiration and photosynthesis (14). Over diverse eukaryotic phyla mitochondria and chloroplasts, either alone or together, provide a concerted amplification of cellular energy production via conserved biochemical pathways that have been positively enhanced in their catalytic and regulatory capacities during evolution.

It has been well established in the scientific literature that the cellular dysregulation of these two distinct organelles may generate potentially dangerous reactive oxygen species (ROS) due to compromised complex bioenergetics energy production, systemic oxidative stress and compounded pro-inflammatory processes in animals (511). Importantly, the genetically- or biochemically-mediated failure of mitochondrial function in human populations represents a potentially dire event in the etiology of major disease states that include type II diabetes, atherosclerosis, rheumatoid arthritis, Alzheimer's disease and cancer progression (1228). These compelling mechanistic and clinical data suggest that the extent of mitochondrial/chloroplast regulatory signaling may vary over the lifetime of the eukaryotic cell and/or on a moment to moment basis, according to physiological demand and bioenergetics requirements (2830).

Interestingly, a tumor cell may be viewed as a phenotypic reversion to the last common eukaryotic ancestor of the host cell, i.e., a facultative anaerobic microbe with unlimited replication potential (31). For example, anaerobic mitochondria in gill cilia of Mytilus edulis have evolved to utilize the phenotype of a facultative anaerobe, demonstrating that this primitive type of respiration has been evolutionarily conserved (32,33). Accordingly, anaerobically functioning mitochondria may represent a re-emergence or evolutionary retrofit of primordial metabolic processes and a reasonably posed scientific question may relate to the frequency of this state-dependent phenomenon during the lifetime of an organism (2).

2. Co-identities within mitochondria and chloroplasts

It becomes readily apparent that the basic architectonic features of the mitochondrion also permit discrete microenvironments with specialized and autonomously segregated biochemical pathways (34). Given the spectrum of evolutionarily conserved chemical substrates and signaling molecules within TCA (Krebs) cycles and respiratory complexes of functional mitochondria across diverse cell types, it is not surprising that additional points of regulation are continuously emerging (3,35). Furthermore, the presence of functional mitochondria in both plant and animal cells underlines the molecular identities of shared regulatory, bioenergetics and chemical substrate pathways (3,35). The primacy of optimized energy processing in both plant and animal cells is supported by the observation that functional chloroplasts are found in selected animal cell types. The discovery of kleptoplasty, i.e., the dual expression of functional mitochondria and chloroplasts within specialized non-photosynthetic host cells has been extensively studied in the metazoan sacoglossan sea slug (3639). The sacoglossan sea slug extracts and incorporates functional chloroplasts from Ulvophyceae into selected gut cell types (40), thereby allowing derived 'food' sources to be accumulated over time. The dependence on specific strains of algae suggests that strong adaptation mechanisms underlie the successful realization of bidirectional regulatory processes responsible for these requisite synergistic cellular phenomena (41). In conclusion, the dual expression of mitochondria and functional chloroplasts within specialized animal cells indicates a high degree of biochemical identity, stereo selectivity, and conformational matching that are the likely keys to their functional presence and essential endosymbiotic activities for over 2.5 billion years.

Interestingly, the ability of a phototroph to function intracellularly within a representative invertebrate, i.e., the sacoglossan sea slug, was identified as a unique phenomenon unlikely to occur in vertebrates (3640). This working hypothesis, however, was overturned by the observation of internalized algae within embryonic tissues of the spotted salamander (42) and suggests that developmental processes within a vertebrate organism may also require photosynthetic endosymbiosis as an internal regulator. In effect, it appears that green algae and spotted salamander embryos have established an intimate endosymbiotic relationship that permit algae to invade the embryonic tissues and cells of the salamander and eventually degrade as the larvae develop over time (42). Although endosymbiotic algal cells go through degradation, the cells can also encyst on the inner capsule wall which is detected through 18s rDNA amplification in the reproductive tracts of the adult salamanders, thereby allowing for generational transfer of genes (42). Due to the dense accumulation of algae within the embryo, a distinct green color is exhibited, which leads to beneficial effects for the embryo. Requisite physiological effects include lowering embryonic mortality, a larger embryo size and earlier hatching times. It is still unclear as to whether the algae and the embryo have a true bidirectional symbiotic relationship, as there is evidence that the algae have no increase in oxygen levels, although they may benefit from the embryos when their nitrogenous waste is released. In any event, this phenomenon defines a distinctive relationship between developmental processes in a defined vertebrate organism and eukaryotic algae.

A careful examination of the biomedical literature has yielded many examples of biochemical and molecular commonalities between mitochondria and chloroplasts with regard to energy production. A prime biochemical example is the Qo motif in cytochrome b (cyt b), formally known as the PEWY motif in mitochondrial complexes that possesses a high degree of catalytic importance within ordered electron transport complexes. Comprehensive evolutionary sequence analysis of the cyt b Qo motif shows significant substitution within the tetra peptide sequence (PDWY, PPWF, PVWY and PEWY) according to phylogenetically specific patterns (43). The Qo motif has been identified as PEWY in mitochondria and chloroplasts, as PDWY in Gram-positive bacteria, Deinococcus-Thermus and halo archaea, and as PVWY in β- and γ-proteobacteria patterns (43). It appears that the differential expression of PEWY by mitochondria and chloroplasts and PDWY by Gram-positive bacteria is functionally entrained to the redox potential of quinone, thereby reflecting an evolutionary modification from low to high potential electron-transfer systems in the emerging oxygenic atmosphere (43). The molecular evolution of the catalytic Qo quinol oxidation site of cyt b complexes, in particular the tetra peptide PEWY sequence, functionally underlies the common retention of a chemiosmotic proton gradient mechanism for ATP synthesis in cellular respiration and photosynthesis.

In plants, the dynamic relationship between photosynthetic and respiratory processes can vary according to physiological or developmental demands. For example, when tomato fruit ripen, their chloroplasts are functionally differentiated into photosynthetically inactive chromoplasts that can produce ATP through a process known as chromo respiration (44). Similar to mitochondrial respiration, heightened O2 consumption is driven by the concentrations of reduced NADH and NADPH as key electron donors, and is sensitive to the plastid terminal oxidase inhibitor, octyl gallate. Isolated chromoplasts are also sensitive to the cytochrome b6f complex inhibitor, 2,5-dibromo-3-methyl-6-isoproply-p-benzoquinone, thereby indicating heightened electron transport coupled to ATP production concurrent with the ripening process (44). Finally, the number of functionally active mitochondria in fruit tissue was observed to decrease during ripening, consistent with the enhanced contribution of chromoplasts to total ATP production (44).

The essential role of molecular oxygen as the ultimate acceptor in the electron transport chain in animal and plant mitochondria is critically dependent on the integrity of cellular respiratory processes. In contrast to animal systems, it has been well established that plants lack active transport machinery to achieve adequate O2 distribution to all cellular compartments, since gradients within plant tissues are vulnerable to severe hypoxic perturbations with potential dire functional endpoints. In effect, plants require different physiological responses to manage temporal variations in O2 saturation with metabolic adaptations in energy requirements. Thus, an altered physiological demand under hypoxic stress may be coupled to the activation of the cellular glycolytic pathway to generate substrate level ATP production when oxidative phosphorylation is compromised. Therefore, the regulated production of ATP, via anaerobic respiratory mechanisms, requires the co-ordinate recruitment of biochemical and molecular components of the oxygen-sensing pathway in plants, notably selective gene expression of different isoforms of glycolytic enzymes that are functionally adapted to hypoxic conditions, as well as the activation of transcription factors that regulate individual members of other hypoxia-inducible genes (45,46).

In this regard, cellular O2 concentrations have been demonstrated to regulate the expression of group VII ethylene response factors (ERFVIIs), a family of plant-specific transcription factors that are stabilized during hypoxia, but degraded during normoxic conditions, via targeting to the N-end rule pathway of selective proteolysis (4649). ERFVIIs are subsequently involved in the regulation of hypoxia-inducible genes that include HRE1 and HRE2, thereby providing an adaptive homeostatic sensor of O2 deprivation in plants. The N-end rule signaling pathway represents a cellular response mechanism that requires ubiquitin ligation linked to proteasome degradation via covalent modification of N-terminal amino acids. A recent study determined that the conserved N-terminal domain of ERFVIIs also distinguishes them as nitric oxide (NO)-dependent substrates of the N-end rule pathway of targeted proteolysis (50). It therefore appears that the state-dependent expression of ERFVIIs coordinately regulates homeostatic sensing to O2 concentration, as well as key NO-dependent cellular processes.

Finally, the array of complex control mechanisms by which organelle gene expression (OGE) promotes respiration, photosynthesis and plant development is actively under investigation (51). Presently, several required components have been identified that are functionally associated with OGE processes. Nuclear-encoded proteins play important roles in OGE by promoting various required functions such as splicing, transcription, RNA processing and the regulation of translational processes. Normative OGE is regulated by the family of mitochondrial transcription termination factors (mTERF), and the observed dual regulatory targeting of nuclear mitochondrial and chloroplast gene expression by mTERF proteins, supports contentions of convergent evolutionary development. In conclusion, the dual regulatory targeting of mitochondrial and chloroplast gene expression by mTERF proteins to promote optimal energy production and oxygen consumption further advances the evolutionary importance of OGE processes.

It is now established that a similar set of functional genes are encoded in both the plastid and mitochondrial genomes that express catalytically conserved protein subunits within the electron transport chain (52). This implies that OGE processes are critically linked to shared stereo-selective enzyme reactions within common biochemical pathways (41). As an example of parallel and convergent evolution (52), ongoing processes that determine biologically meaningful modification of the OGE may be entrained to regulatory stability of intracellular and intra-mitochondrial redox potential. As such, any hypothesis of the evolutionary modification of the coordinate regulation of redox potential should predict discrete cellular loci for membrane proteins that are functionally related to respiratory and/or photosynthetic processes (52). Furthermore, the dual evolution of the plastid and mitochondria genomes will effectively drive the retention of functionally similar set of ribosomal protein genes which are functionally required for proper ribosomal assembly.

3. Antibiotic usage and mitochondrial dysfunction from an evolutionary perspective

Clinically employed classes of antibiotics represent the primary arsenal of chemical agents used to treat bacterial infections. Between 1940 and 1962, 20 novel classes of antibiotics were discovered and vary with regard to their structure and mechanism of action (53). The bactericidal effects of various antibiotics are possibly mediated by the induction of damaging ROS (54,55). A recent key study determined that bactericidal antibiotics elevate O2 consumption, thereby altering bacterial redox physiology to produce lethal concentrations of ROS (55). As a critical control, the bactericidal efficacy of antibiotics was observed to decrease under strict anaerobic conditions, an effect that could be reversed by exposure to O2 or equivalent electron acceptors. The overall importance of these observations relates to an expanded mechanism of action, whereby bactericidal antibiotics promote complex redox alterations that contribute to cellular damage and death, while also underlining a common evolutionary and developmental linkage between primordial bacteria and mitochondria (56,57).

Despite their number and various mechanisms of action, bacterial resistance has markedly limited widespread unrestricted usage of previously efficacious antibiotics (58). As alluded to above, additional limitations on the usage of certain classes of antibiotics relates to their documented side-effects functionally linked to mitochondrial dysfunction. As a prime example, aminoglycoside antibiotics used to treat infections of the inner ear (59) have been shown to irreversibly damage sensory hair cells due to the excessive production of mitochondria-derived ROS (3,18,24,29,6062). Furthermore, the widely used class of tetracycline derivatives presents significant risk to patients with compromised mitochondrial functioning (63) due to established inhibitory effects on mitochondrial translational activities, including targeting of ribosomal RNA (64) that result in 'proteotoxic' stress and compensatory changes in nuclear gene expression (65). Interestingly, the selective targeting of mitochondrial translational apparatus by low concentrations of tetracyclines may in fact reiterate the evolutionary and developmental links between mitochondria and proteobacteria expression (65,66).

The glycopeptide antibiotic vancomycin chloride is widely used for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Nephrotoxicity, however, has been observed as a major adverse effect of vancomycin usage, thereby limiting the utility of the antibiotic in selected cases (67). A proposed mechanism of action was derived from a recent in vitro study demonstrating vancomycin-induced apoptotic renal tubular cell death driven by enhanced mitochondrial-derived ROS production linked to the inhibition of mitochondrial complex I activity (68). The results of this study were complemented by those of an earlier study demonstrating enhancements in complement-related and pro-inflammatory gene expression associated with oxidative cellular damage in kidney tissues of female rats following the administration of high concentrations of vancomycin (69).

It is worth noting that 'reverse engineering' of antibiotic-induced mitochondrial dysfunction has been proposed and pre-clinically employed as a therapeutic strategy against various malignant cell types, including cancer stem cells (7074). Importantly, several classes of FDA-approved, widely employed, antibiotics including the erythromycins, the tetracyclines and the glycylcyclines have been shown to be highly effective anti-proliferative agents against cancer stem cells in 12 different cell lines via the inhibition of mitochondrial biogenesis linked to anabolic processes (74). Interestingly, in this same study, the authors proposed to treat cancer according to an infectious disease paradigm, utilizing a therapeutic regimen consisting of mitochondrial targeting by selected antibiotics. As a corollary, it has been recently demonstrated that the widely administered tetracycline analog, doxycycline, downregulates DNA repair mechanisms in cancer stem cells that are functionally linked to the maintenance of mtDNA integrity and copy number (72). Mechanistically, it was also shown that doxycycline treatment quantitatively reduced nuclear respiratory factor (NRF)1/2-mediated antioxidant responses and effectively inhibited multiple cancer stem cell signaling pathways. By contrast, the broad spectrum antibiotic, chloramphenicol, previously demonstrated to inhibit both mitochondrial protein expression and ATP production, may stimulate tumor progression via the activation of c-Jun N-terminal kinase (JNK) and phos-phoinositide 3-kinase (PI3K) signaling pathways, leading to enhanced matrix metalloproteinase-13 region (MMP-13) gene expression (75,76). In conclusion, the translational potential of selected classes of antibiotics as anti-cancer agents must be evaluated by multiple physiological criteria, including inhibition of normative mitochondrial functioning.

4. Antibiotic usage and acute behavioral disorders: Potential association with mitochondrial dysfunction

A 2002 publication reviewed the incidence of acute manic episodes subsequent to antibiotic usage, subsequently termed 'antibiomania', as documented in 21 published studies, 82 cases reported by the World Health Organization (WHO), and unpublished data supplied by the Food and Drug Administration (FDA) (77). In total, usage of the erythromycin derivative, clar-ithromycin, was implicated in 28% of reported cases, whereas usage of the fluoroquinolones ciprofloxacin and ofloxacin was implicated in 27% of reported cases. These reports were consistent with unpublished FDA data indicating clarithromycin and ciprofloxacin usage to be most frequently associated with the development of acute manic episodes and were supported by additional studies exclusively focusing on the involvement of ciprofloxacin (7880), oflaxocin (81) and clarithromycin (82,83) in the induction of acute psychotic episodes.

Mechanistically, it has been proposed that the stereoselective binding of ciprofloxacin to a mitochondrion-associated subtype of the NMDA receptor (84) promotes psycho-affective behavioral effects similar to those produced by the administration of dissociative anesthetics via the calcium-dependent excitation of hippocampal subfields (85). Conversely, the cipro-floxacin/fluoriquinolone-mediated inhibition of GABA-ergic signaling, partially driven via the production of mitochondrial ROS (86), has been shown to result in excitatory pro-convulsive neuronal activation as a putative contributing factor to the presentation of acute psychotic episodes (8789). Subsequent case reports have observed acute psychotic/manic episodes following the administration of the nitroimidazole antibiotic, metronidazole (81), the mixed folate inhibitor/sulfonamide antibiotic cotrimoxazole (9092), and the third generation cephalosporin derivatives ceftazidime (93) and ceftriaxone (94). Based on the diversity of the chemical structure and mode of action inherent to each class of antibiotic, a generalized downregulation of mitochondrial bioenergetics may account for the integrated psycho-affective behavioral effects observed in the string of case reports cited above. It would also appear likely that previous studies linking the acute psychotic effects of fluoroquinolones to interactions with NMDA and/or GABA-ergic neural transmission can be attributed to acute metabolic rundown due to severe mitochondrial inhibition (7881).

5. Mitochondrial dysfunction in psychiatric disorders

The emergence of a highly efficient mitochondrial-driven ATP production appears to be a requisite component for the development of evolutionary diverse networking systems within the central nervous system (CNS) of higher animals, e.g., cognition appears to be rare. The manifestation of compromised cellular energy production, either due to oxidative stress and compounded pro-inflammation, hypoxia or genetically- or biochemically-determined mitochondrial abnormalities represents a major contributing factor to the symptomatology of major psychiatric illnesses, including major depressive disorder, bipolar disorder and schizophrenia (1,62,95). As a corollary, increases in the prevalence of neuropsychiatric disorders within aging adult populations suggest that the proto-symbiotic relationship of cellular mitochondria to compounded CNS energy production linked to entrainment of complex behaviors may be markedly altered within the lifetime of an individual. As with other metabolic processes, aberrantly high levels of ROS have been linked to cell death and degeneration in relatively diverse CNS pathophysiologies, including Alzheimer's disease, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD) and bipolar personality disorder (BPD) (96102).

Mechanistically, causative factors involved in acute and chronic CNS damage linked to complex behavioral sequelae include high levels of mitochondrial-associated pro-oxidant iron functionally linked to lipid peroxidation (103106) and ultimately enhanced endonuclease-mediated DNA fragmentation (107). Enhanced mitochondrial uptake of calcium linked to enhanced ROS production (108112) has been established as a key causative factor in neurodegenerative conditions (98,113120), as well as major psychiatric illnesses including schizophrenia (SCZ) (99,101,121123). Chronic oxidative stress in conjunction with altered NO-mediated signaling pathways has also been proposed as a significant contributing factor in the pathophysiology of SCZ-related behaviors (124,125) and in the etiology of BPD (126). Etiological factors involving mitochondrial dysfunction in the presentation of BPD- and SCZ-related symptomatologies reveals a reduction in the gene expression of essential electron transport chain subunits (127).

Dysfunctional GMP-PKG signaling (116,128,129) and NOX2-mediated processes (130) also are causative factors in the pathogenesis of diverse psychiatric disorders (130). Abnormalities associated with the electron transport chain system and the mitochondrial complex may be involved in the etiology of autism spectrum disorder (ASD) (102,131,132). Additional mitochondrial-associated pathophysiological factors in the development of ASD include altered pyruvate dehydrogenase activity and mtDNA copy numbers and enhanced oxidative stress (102,131,133,134). Finally, CNS antioxidant glutathione deficiency has also been functionally linked to autistic behaviors (131,135) and in SCZ and BPD (136).

In light of the above, we previously hypothesized that the multi-enzyme biosynthetic pathway responsible for endogenous morphine in animal cells may be similarly compromised in neuropsychiatric disorders due to their dependence on dopamine as a major synthetic precursor (137,138). Morphine administration engenders inhibitory effects on neuronal excitation and associated integrated behaviors that are consistent with coordinate regulatory activities on mitochondrial respiration, O2 consumption, and aerobic ATP synthesis (139). Furthermore, the metabolic effects of endogenous morphine on CNS mitochondrial functions are selectively mediated by a novel 6-transmembrane domain GPCR, the mu-3 opiate receptor subtype, that is functionally coupled to constitutive NO production and release (139145). The multi-faceted regulatory role of mitochondrial NO on O2 consumption, oxidative phosphorylation, and ATP production reinforce the biological importance of morphine-coupled regulatory responses in integrated CNS behavioral pathways and their dysregulation in oxidative stress-associated neuropsychiatric disorders (95). Accordingly, endogenous morphine expression, which exerts its cellular actions via novel membrane G-coupled receptors, is directly responsible for overall cellular integrity via its regulation of mitochondrial respiration and functional linkage to NO production and release (138).

6. Conclusions and translational insights

As noted earlier, the dual expression of mitochondria and functional chloroplasts within specialized animal cells indicates a high degree of biochemical identity, stereoselectivity and conformational matching that are the likely keys to their functional presence, tolerance and essential endosymbiotic activities for billions of years (3,35,41,146,147). It has been recently proposed that archaebacterial and eubacterial precursors led to the origin of eukaryotes (148,149). Mitochondria arose via bidirectional endosymbiotic selection processes from an entrapped α-proteobacterium within a primordial eukaryotic cell (149,150). Plastids arose in a similar manner, but from an entrapped cyanobacterium within a eukaryotic precursor cell (149). Hence, eukaryotic cell types of higher organisms were evolutionarily fashioned to express autonomously contained bioenergetics processing centers in the form or mitochondria or chloroplasts.

The developmental primacy of photosynthesis was probably due to abundant sunlight and the coincident appearance of requisite photovoltaic chemical processes. Furthermore, the global abundance of reduced carbon in the form of glucose with concurrent expansion of atmospheric O2 concentration introduced a major change in the biosphere, thereby driving evolutionary development of complex cellular respiratory processes along with major potential problems involving O2 toxicity. In light of these changes, both photosynthetic and respiratory processes were driven by the potential for endosymbiotic protobacteria to evolve into semi-autonomous cellular organelles with concentrated catalytic foci expressed as highly ordered membrane protein complexes capable of errorless electron transport.

It has been proposed that the respiratory 'bacterium' evolved and remained in place because of its existential brokerage of molecular oxygen and the use of glucose as an initial fuel source within the metabolic pathway terminating in chemiosmotic ATP production. In this regard, photosynthetic priming events promoted evolutionary acceleration of intracellular membrane differentiation, selective for plastid-like structures. This major contention is supported by the observation that many organelles can be found in both plant and animal cells and that their molecular biology/bioenergetics share basic chemical processes (3,35,41).

Concerted biochemical and molecular investigation of the human gut microbiome is necessary to elucidate complex regulatory activities that directly affect diverse physiological activities of the 'host' organism (151153). Given this multifaceted complex nature of the relationship between gut bacteria and humoral CNS factors, it is a highly reasonable contention that the gut microbiome is playing a role in the initiation and sustainability of normal and abnormal behaviors (153). Whereas normative microbiome activities represent key contributing factors to ongoing diverse physiological activities, severe perturbations of gut microbiota resulting in mucosal dysbiosis (154,155) are associated with pathological conditions that include gastrointestinal disease, obesity, and type II diabetes and ASD (156). The regulatory influences of the human gut microbiome also extend to immune activation and neuroimmune communication. In a pathophysiological setting, microbiotic dysregulation may inappropriately stimulate macrophage penetration into the CNS, with concurrent activation of proinflammatory processes involving activated microglia (157). Counter-intuitively, given the 10X greater number of gut bacteria in comparison to eukaryotic cells, which also contain evolutionarily derived mitochondria, it would appear that the summated populations of 'simple' organisms may in fact regulate the ultimate fate of our genetic material. In sum, it has become compellingly apparent that eukaryotic cells and complex organ systems cannot survive without the synergistic complex interactions of competent enteric bacteria and evolutionarily fashioned mitochondria.

Acknowledgments

The present study was, in part, funded by MitoGenetics, LLC (Sioux Falls, SD, USA).

References

1 

Stefano GB and Kream R: Psychiatric disorders involving mitochondrial processes. Psychol Obs. 1:1–6. 2015.

2 

Stefano GB, Mantione KJ, Casares FM and Kream RM: Anaerobically functioning mitochondria: Evolutionary perspective on modulation of energy metabolism in Mytilus edulis. Invertebrate Surviv J. 12:22–28. 2015.

3 

Snyder C and Stefano GB: Mitochondria and chloroplasts shared in animal and plant tissues: Significance of communication. Med Sci Monit. 21:1507–1511. 2015. View Article : Google Scholar : PubMed/NCBI

4 

Mantione K, Kream RM and Stefano GB: Variations in critical morphine biosynthesis genes and their potential to influence human health. Neuro Endocrinol Lett. 31:11–18. 2010.PubMed/NCBI

5 

Esch T and Stefano G: Proinflammation: A common denominator or initiator of different pathophysiological disease processes. Med Sci Monit. 8:HY1–HY9. 2002.PubMed/NCBI

6 

Takahashi E and Sato M: Anaerobic respiration sustains mitochondrial membrane potential in a prolyl hydroxylase pathway-activated cancer cell line in a hypoxic microenvironment. Am J Physiol Cell Physiol. 306:C334–C342. 2014. View Article : Google Scholar

7 

Gonzalez MJ, Miranda Massari JR, Duconge J, Riordan NH, Ichim T, Quintero-Del-Rio AI and Ortiz N: The bio-energetic theory of carcinogenesis. Med Hypotheses. 79:433–439. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Chen Z and Stamler JS: Bioactivation of nitroglycerin by the mitochondrial aldehyde dehydrogenase. Trends Cardiovasc Med. 16:259–265. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Müller M, Mentel M, van Hellemond JJ, Henze K, Woehle C, Gould SB, Yu RY, van der Giezen M, Tielens AG and Martin WF: Biochemistry and evolution of anaerobic energy metabolism in eukaryotes. Microbiol Mol Biol Rev. 76:444–495. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Watt IN, Montgomery MG, Runswick MJ, Leslie AG and Walker JE: Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proc Natl Acad Sci USA. 107:16823–16827. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Degli Esposti M: Bioenergetic evolution in proteobacteria and mitochondria. Genome Biol Evol. 6:3238–3251. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Aliev G, Priyadarshini M, Reddy VP, Grieg NH, Kaminsky Y, Cacabelos R, Ashraf GM, Jabir NR, Kamal MA, Nikolenko VN, et al: Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease. Curr Med Chem. 21:2208–2217. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Carvalho C, Machado N, Mota PC, Correia SC, Cardoso S, Santos RX, Santos MS, Oliveira CR and Moreira PI: Type 2 diabetic and Alzheimer's disease mice present similar behavioral, cognitive, and vascular anomalies. J Alzheimers Dis. 35:623–635. 2013.PubMed/NCBI

14 

Chong ZZ, Li F and Maiese K: Oxidative stress in the brain: Novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol. 75:207–246. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Ebadi M, Govitrapong P, Sharma S, Muralikrishnan D, Shavali S, Pellett L, Schafer R, Albano C and Eken J: Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of Parkinson's disease. Biol Signals Recept. 10:224–253. 2001. View Article : Google Scholar : PubMed/NCBI

16 

Kream RM, Mantione KJ, Casares FM and Stefano GB: Impaired expression of ATP-binding cassette transporter genes in diabetic ZDF rat blood. Int J Diabetes Res. 3:49–55. 2014.

17 

Kream RM, Mantione KJ, Casares FM and Stefano GB: Concerted dysregulation of 5 major classes of blood leukocyte genes in diabetic ZDF rats: A working translational profile of comorbid rheumatoid arthritis progression. Int J Prev Treat. 3:17–25. 2014.

18 

Wang F, Guo X, Shen X, Kream RM, Mantione KJ and Stefano GB: Vascular dysfunction associated with type 2 diabetes and Alzheimer's disease: A potential etiological linkage. Med Sci Monit Basic Res. 20:118–129. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Wang F, Stefano GB and Kream RM: Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: Etiological contribution to complex regional pain syndromes (Part I). Med Sci Monit. 20:1067–1077. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Wang F, Stefano GB and Kream RM: Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: Etiological contribution to complex regional pain syndromes (Part II). Med Sci Monit. 20:1188–1200. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Panksepp J, Herman B, Conner R, Bishop P and Scott JP: The biology of social attachments: Opiates alleviate separation distress. Biol Psychiatry. 13:607–618. 1978.PubMed/NCBI

22 

Pierce RC and Kumaresan V: The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev. 30:215–238. 2006. View Article : Google Scholar

23 

Schmauss C and Emrich HM: Dopamine and the action of opiates: A reevaluation of the dopamine hypothesis of schizophrenia. With special consideration of the role of endogenous opioids in the pathogenesis of schizophrenia. Biol Psychiatry. 20:1211–1231. 1985. View Article : Google Scholar : PubMed/NCBI

24 

Stępień A, Stępień M, Wlazeł RN, Paradowski M, Banach M and Rysz J: Assessment of the relationship between lipid parameters and obesity indices in non-diabetic obese patients: A preliminary report. Med Sci Monit. 20:2683–2688. 2014. View Article : Google Scholar

25 

Göhring I, Sharoyko VV, Malmgren S, Andersson LE, Spégel P, Nicholls DG and Mulder H: Chronic high glucose and pyruvate levels differentially affect mitochondrial bioenergetics and fuel-stimulated insulin secretion from clonal INS-1 832/13 cells. J Biol Chem. 289:3786–3798. 2014. View Article : Google Scholar :

26 

Mantione KJ, Kream RM, Kuzelova H, Ptacek R, Raboch J, Samuel JM and Stefano GB: Comparing bioinformatic gene expression profiling methods: Microarray and RNA-Seq. Med Sci Monit Basic Res. 20:138–142. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Kram KE and Finkel SE: Culture volume and vessel affect long-term survival, mutation frequency, and oxidative stress of Escherichia coli. Appl Environ Microbiol. 80:1732–1738. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Stefano GB and Kream RM: Hypoxia defined as a common culprit/initiation factor in mitochondrial-mediated proinflammatory processes. Med Sci Monit. 21:1478–1484. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Guo R, Li W, Liu B, Li S, Zhang B and Xu Y: Resveratrol protects vascular smooth muscle cells against high glucose-induced oxidative stress and cell proliferation in vitro. Med Sci Monit Basic Res. 20:82–92. 2014. View Article : Google Scholar : PubMed/NCBI

30 

Yildirim V, Doganci S, Yesildal F, Kaya E, Ince ME, Ozkan G, Gumusel B, Avcu F and Ozgurtas T: Sodium nitrite provides angiogenic and proliferative effects in vivo and in vitro. Med Sci Monit Basic Res. 21:41–46. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Davila AF and Zamorano P: Mitochondria and the evolutionary roots of cancer. Phys Biol. 10:0260082013. View Article : Google Scholar : PubMed/NCBI

32 

Doeller JE, Grieshaber MK and Kraus DW: Chemolithoheterotrophy in a metazoan tissue: Thiosulfate production matches ATP demand in ciliated mussel gills. J Exp Biol. 204:3755–3764. 2001.PubMed/NCBI

33 

Doeller JE, Kraus DW, Shick JM and Gnaiger E: Heat flux, oxygen flux, and mitochondrial redox state as a function of oxygen availability and ciliary activity in excised gills of Mytilus edulis. J Exp Zool. 265:1–8. 1993. View Article : Google Scholar : PubMed/NCBI

34 

Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D and Reiter RJ: Mitochondria and chloroplasts as the original sites of melatonin synthesis: A hypothesis related to melatonin's primary function and evolution in eukaryotes. J Pineal Res. 54:127–138. 2013. View Article : Google Scholar

35 

Stefano GB, Snyder C and Kream RM: Mitochondria, chloroplasts in animal and plant cells: Significance of conformational matching. Med Sci Monit. 21:2073–2078. 2015. View Article : Google Scholar : PubMed/NCBI

36 

Cruz S, Calado R, Serôdio J and Cartaxana P: Crawling leaves: Photosynthesis in sacoglossan sea slugs. J Exp Bot. 64:3999–4009. 2013. View Article : Google Scholar : PubMed/NCBI

37 

Serôdio J, Cruz S, Cartaxana P and Calado R: Photophysiology of kleptoplasts: Photosynthetic use of light by chloroplasts living in animal cells. Philos Trans R Soc Lond B Biol Sci. 369:201302422014. View Article : Google Scholar : PubMed/NCBI

38 

de Vries J, Christa G and Gould SB: Plastid survival in the cytosol of animal cells. Trends Plant Sci. 19:347–350. 2014. View Article : Google Scholar : PubMed/NCBI

39 

Pennisi E: Microbiology. Modern symbionts inside cells mimic organelle evolution. Science. 346:532–533. 2014. View Article : Google Scholar : PubMed/NCBI

40 

Händeler K, Wägele H, Wahrmund U, Rüdinger M and Knoop V: Slugs' last meals: Molecular identification of sequestered chloroplasts from different algal origins in Sacoglossa (Opisthobranchia, Gastropoda). Mol Ecol Resour. 10:968–978. 2010. View Article : Google Scholar

41 

Stefano GB: Conformational matching: a possible evolutionary force in the evolvement of signal systems. CRC Handbook of Comparative Opioid and Related Neuropeptide Mechanisms. Stefano GB: CRC Press Inc; Boca Raton: pp. 271–277. 1986

42 

Kerney R, Kim E, Hangarter RP, Heiss AA, Bishop CD and Hall BK: Intracellular invasion of green algae in a salamander host. Proc Natl Acad Sci USA. 108:6497–6502. 2011. View Article : Google Scholar : PubMed/NCBI

43 

Kao WC and Hunte C: The molecular evolution of the Qo motif. Genome Biol Evol. 6:1894–1910. 2014. View Article : Google Scholar : PubMed/NCBI

44 

Renato M, Pateraki I, Boronat A and Azcón-Bieto J: Tomato fruit chromoplasts behave as respiratory bioenergetic organelles during ripening. Plant Physiol. 166:920–933. 2014. View Article : Google Scholar : PubMed/NCBI

45 

Bailey-Serres J and Voesenek LA: Flooding stress: Acclimations and genetic diversity. Annu Rev Plant Biol. 59:313–339. 2008. View Article : Google Scholar : PubMed/NCBI

46 

Gibbs DJ, Lee SC, Isa NM, Gramuglia S, Fukao T, Bassel GW, Correia CS, Corbineau F, Theodoulou FL, Bailey-Serres J and Holdsworth MJ: Homeostatic response to hypoxia is regulated by the N-end rule pathway in plants. Nature. 479:415–418. 2011. View Article : Google Scholar : PubMed/NCBI

47 

Xu K, Xu X, Fukao T, Canlas P, Maghirang-Rodriguez R, Heuer S, Ismail AM, Bailey-Serres J, Ronald PC and Mackill DJ: Sub1A is an ethylene-response-factor-like gene that confers submergence tolerance to rice. Nature. 442:705–708. 2006. View Article : Google Scholar : PubMed/NCBI

48 

Fukao T, Yeung E and Bailey-Serres J: The submergence tolerance regulator SUB1A mediates crosstalk between submergence and drought tolerance in rice. Plant Cell. 23:412–427. 2011. View Article : Google Scholar : PubMed/NCBI

49 

van Dongen JT and Licausi F: Oxygen sensing and signaling. Annu Rev Plant Biol. 66:345–367. 2015. View Article : Google Scholar : PubMed/NCBI

50 

Gibbs DJ, Conde JV, Berckhan S, Prasad G, Mendiondo GM and Holdsworth MJ: Group VII ethylene response factors coordinate oxygen and nitric oxide signal transduction and stress responses in plants. Plant Physiol. 169:23–31. 2015. View Article : Google Scholar : PubMed/NCBI

51 

Kleine T and Leister D: Emerging functions of mammalian and plant mTERFs. Biochim Biophys Acta. 1847:786–797. 2015. View Article : Google Scholar : PubMed/NCBI

52 

Maier UG, Zauner S, Woehle C, Bolte K, Hempel F, Allen JF and Martin WF: Massively convergent evolution for ribosomal protein gene content in plastid and mitochondrial genomes. Genome Biol Evol. 5:2318–2329. 2013. View Article : Google Scholar : PubMed/NCBI

53 

Coates AR, Halls G and Hu Y: Novel classes of antibiotics or more of the same? Br J Pharmacol. 163:184–194. 2011. View Article : Google Scholar : PubMed/NCBI

54 

Kalghatgi S, Spina CS, Costello JC, Liesa M, Morones-Ramirez JR, Slomovic S, Molina A, Shirihai OS and Collins JJ: Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in Mammalian cells. Sci Transl Med. 5:192ra852013. View Article : Google Scholar : PubMed/NCBI

55 

Dwyer DJ, Belenky PA, Yang JH, MacDonald IC, Martell JD, Takahashi N, Chan CT, Lobritz MA, Braff D, Schwarz EG, et al: Antibiotics induce redox-related physiological alterations as part of their lethality. Proc Natl Acad Sci USA. 111:E2100–E2109. 2014. View Article : Google Scholar : PubMed/NCBI

56 

Gray MW, Burger G and Lang BF: The origin and early evolution of mitochondria. Genome Biol. 2:reviews1018.1–reviews1018.5. 2001. View Article : Google Scholar

57 

Zimorski V, Ku C, Martin WF and Gould SB: Endosymbiotic theory for organelle origins. Curr Opin Microbiol. 22:38–48. 2014. View Article : Google Scholar : PubMed/NCBI

58 

Powers JH: Antimicrobial drug development - the past, the present, and the future. Clin Microbiol Infect. 10(Suppl 4): 23–31. 2004. View Article : Google Scholar

59 

Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qiu WQ, Arnos KS, Cortopassi GA, Jaber L, Rotter JI, et al: Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet. 4:289–294. 1993. View Article : Google Scholar : PubMed/NCBI

60 

Desa D, Nichols MG and Jensen Smith H: The role of complex I in mitochondrial reactive oxygen species formation in cochlear sensory and supporting cells during ototoxic aminoglycoside exposure. Biophys J. 108:611a2015. View Article : Google Scholar

61 

Katsi V, Katsimichas T, Kallistratos MS, Tsekoura D, Makris T, Manolis AJ, Tousoulis D, Stefanadis C and Kallikazaros I: The association of Restless Legs Syndrome with hypertension and cardiovascular disease. Med Sci Monit. 20:654–659. 2014. View Article : Google Scholar : PubMed/NCBI

62 

Stefano GB and Kream RM: Nitric oxide regulation of mitochondrial processes: Commonality in medical disorders. Ann Transplant. 20:402–407. 2015. View Article : Google Scholar : PubMed/NCBI

63 

Jones CN, Miller C, Tenenbaum A, Spremulli LL and Saada A: Antibiotic effects on mitochondrial translation and in patients with mitochondrial translational defects. Mitochondrion. 9:429–437. 2009. View Article : Google Scholar : PubMed/NCBI

64 

Pacheu-Grau D, Gómez-Durán A, Iglesias E, López-Gallardo E, Montoya J and Ruiz-Pesini E: Mitochondrial antibiograms in personalized medicine. Hum Mol Genet. 22:1132–1139. 2013. View Article : Google Scholar

65 

Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG, Mottis A, Jovaisaite V, Frochaux MV, Quiros PM, Deplancke B, et al: Tetracyclines disturb mitochondrial function across eukaryotic models: A call for caution in biomedical research. Cell Rep. 10:1681–1691. 2015. View Article : Google Scholar

66 

Singh R, Sripada L and Singh R: Side effects of antibiotics during bacterial infection: Mitochondria, the main target in host cell. Mitochondrion. 16:50–54. 2014. View Article : Google Scholar

67 

Stevens DL: The role of vancomycin in the treatment paradigm. Clin Infect Dis. 42(Suppl 1): S51–S57. 2006. View Article : Google Scholar

68 

Arimura Y, Yano T, Hirano M, Sakamoto Y, Egashira N and Oishi R: Mitochondrial superoxide production contributes to vancomycin-induced renal tubular cell apoptosis. Free Radic Biol Med. 52:1865–1873. 2012. View Article : Google Scholar : PubMed/NCBI

69 

Dieterich C, Puey A, Lin S, Swezey R, Furimsky A, Fairchild D, Mirsalis JC and Ng HH: Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates. Toxicol Sci. 107:258–269. 2009. View Article : Google Scholar :

70 

Sanchez-Alvarez R, Martinez-Outschoorn UE, Lamb R, Hulit J, Howell A, Gandara R, Sartini M, Rubin E, Lisanti MP and Sotgia F: Mitochondrial dysfunction in breast cancer cells prevents tumor growth: Understanding chemoprevention with metformin. Cell Cycle. 12:172–182. 2013. View Article : Google Scholar :

71 

Lamb R, Harrison H, Hulit J, Smith DL, Lisanti MP and Sotgia F: Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget. 5:11029–11037. 2014. View Article : Google Scholar : PubMed/NCBI

72 

Lamb R, Fiorillo M, Chadwick A, Ozsvari B, Reeves KJ, Smith DL, Clarke RB, Howell SJ, Cappello AR, Martinez-Outschoorn UE, et al: Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy. Oncotarget. 6:14005–14025. 2015. View Article : Google Scholar : PubMed/NCBI

73 

Jayaprakash AD, Benson EK, Gone S, Liang R, Shim J, Lambertini L, Toloue MM, Wigler M, Aaronson SA and Sachidanandam R: Stable heteroplasmy at the single-cell level is facilitated by intercellular exchange of mtDNA. Nucleic Acids Res. 43:2177–2187. 2015. View Article : Google Scholar : PubMed/NCBI

74 

Lamb R, Ozsvari B, Lisanti CL, Tanowitz HB, Howell A, Martinez-Outschoorn UE, Sotgia F and Lisanti MP: Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease. Oncotarget. 6:4569–4584. 2015. View Article : Google Scholar : PubMed/NCBI

75 

Leeman MF, Curran S and Murray GI: The structure, regulation, and function of human matrix metalloproteinase-13. Crit Rev Biochem Mol Biol. 37:149–166. 2002. View Article : Google Scholar : PubMed/NCBI

76 

Li CH, Cheng YW, Liao PL, Yang YT and Kang JJ: Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion. Toxicol Sci. 116:140–150. 2010. View Article : Google Scholar : PubMed/NCBI

77 

Abouesh A, Stone C and Hobbs WR: Antimicrobial-induced mania (antibiomania): A review of spontaneous reports. J Clin Psychopharmacol. 22:71–81. 2002. View Article : Google Scholar : PubMed/NCBI

78 

Ben-Chetrit E, Rothstein N and Munter G: Ciprofloxacin-induced psychosis. Antimicrob Agents Chemother. 57:40792013. View Article : Google Scholar : PubMed/NCBI

79 

Mulhall JP and Bergmann LS: Ciprofloxacin-induced acute psychosis. Urology. 46:102–103. 1995. View Article : Google Scholar : PubMed/NCBI

80 

Reeves RR: Ciprofloxacin-induced psychosis. Ann Pharmacother. 26:930–931. 1992.PubMed/NCBI

81 

Koul S, Bhan-Kotwal S, Jenkins HS and Carmaciu CD: Organic psychosis induced by ofloxacin and metronidazole. Br J Hosp Med (Lond). 70:236–237. 2009. View Article : Google Scholar

82 

Dinca EB, Skinner A, Dinca RV and Tudose C: The dangers of gastritis: A case of clarithromycin-associated brief psychotic episode. J Nerv Ment Dis. 203:149–151. 2015. View Article : Google Scholar : PubMed/NCBI

83 

Jiménez-Pulido I, Navarro-Ruiz A, Sendra P, Martínez-Ramírez M, Garcia-Motos C and Montesinos-Ros A: Hallucinations with therapeutic doses of clarithromycin. Int J Clin Pharmacol Ther. 40:20–22. 2002. View Article : Google Scholar : PubMed/NCBI

84 

Korde AS and Maragos WF: Identification of an N-methyl-D-aspartate receptor in isolated nervous system mitochondria. J Biol Chem. 287:35192–35200. 2012. View Article : Google Scholar : PubMed/NCBI

85 

Schmuck G, Schürmann A and Schlüter G: Determination of the excitatory potencies of fluoroquinolones in the central nervous system by an in vitro model. Antimicrob Agents Chemother. 42:1831–1836. 1998.PubMed/NCBI

86 

Accardi MV, Daniels BA, Brown PM, Fritschy JM, Tyagarajan SK and Bowie D: Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission. Nat Commun. 5:31682014. View Article : Google Scholar : PubMed/NCBI

87 

Kawakami J, Yamamoto K, Asanuma A, Yanagisawa K, Sawada Y and Iga T: Inhibitory effect of new quinolones on GABA(A) receptor-mediated response and its potentiation with felbinac in Xenopus oocytes injected with mouse-brain mRNA: Correlation with convulsive potency in vivo. Toxicol Appl Pharmacol. 145:246–254. 1997. View Article : Google Scholar : PubMed/NCBI

88 

Zhang HYMB, McPherson BC, Liu H, Baman TS, Rock P and Yao Z: H(2)O(2) opens mitochondrial K(ATP) channels and inhibits GABA receptors via protein kinase C-epsilon in cardio-myocytes. Am J Physiol Heart Circ Physiol. 282:H1395–H1403. 2002. View Article : Google Scholar : PubMed/NCBI

89 

Grill MF and Maganti RK: Neurotoxic effects associated with antibiotic use: Management considerations. Br J Clin Pharmacol. 72:381–393. 2011. View Article : Google Scholar : PubMed/NCBI

90 

Stuhec M: Trimethoprim-sulfamethoxazole-related hallucinations. Gen Hosp Psychiatry. 36:230.e237–e238. 2014. View Article : Google Scholar

91 

Weis S, Karagülle D, Kornhuber J and Bayerlein K: Cotrimoxazole-induced psychosis: A case report and review of literature. Pharmacopsychiatry. 39:236–237. 2006. View Article : Google Scholar : PubMed/NCBI

92 

Lee KY, Huang CH, Tang HJ, Yang CJ, Ko WC, Chen YH, Lee YC and Hung CC: Acute psychosis related to use of trimethoprim/sulfamethoxazole in the treatment of HIV-infected patients with Pneumocystis jirovecii pneumonia: A multicentre, retrospective study. J Antimicrob Chemother. 67:2749–2754. 2012. View Article : Google Scholar : PubMed/NCBI

93 

Quandt-Herrera P, Suarez-Jesus J and Yelmo-Cruz S: Antibiomania: Secondary mania associated with ceftazidime. J Clin Psychopharmacol. 35:619–621. 2015. View Article : Google Scholar : PubMed/NCBI

94 

Landais A, Marty N, Bessis D, Pages M and Blard JM: Hoigne syndrome following an intravenous injection of ceftriaxone: A case report. Rev Med Interne. 35:199–201. 2014.In French. View Article : Google Scholar

95 

Stefano GB, Kim C, Mantione K, Casares F and Kream RM: Targeting mitochondrial biogenesis for promoting health. Med Sci Monit. 18:SC1–SC3. 2012. View Article : Google Scholar : PubMed/NCBI

96 

Michel TM, Pülschen D and Thome J: The role of oxidative stress in depressive disorders. Curr Pharm Des. 18:5890–5899. 2012. View Article : Google Scholar : PubMed/NCBI

97 

Regenold WT, Pratt M, Nekkalapu S, Shapiro PS, Kristian T and Fiskum G: Mitochondrial detachment of hexokinase 1 in mood and psychotic disorders: Implications for brain energy metabolism and neurotrophic signaling. J Psychiatr Res. 46:95–104. 2012. View Article : Google Scholar

98 

Tobe EH: Mitochondrial dysfunction, oxidative stress, and major depressive disorder. Neuropsychiatr Dis Treat. 9:567–573. 2013. View Article : Google Scholar : PubMed/NCBI

99 

Hovatta I, Juhila J and Donner J: Oxidative stress in anxiety and comorbid disorders. Neurosci Res. 68:261–275. 2010. View Article : Google Scholar : PubMed/NCBI

100 

Andreazza AC: Combining redox-proteomics and epigenomics to explain the involvement of oxidative stress in psychiatric disorders. Mol Biosyst. 8:2503–2512. 2012. View Article : Google Scholar : PubMed/NCBI

101 

Gigante AD, Andreazza AC, Lafer B, Yatham LN, Beasley CL and Young LT: Decreased mRNA expression of uncoupling protein 2, a mitochondrial proton transporter, in post-mortem prefrontal cortex from patients with bipolar disorder and schizophrenia. Neurosci Lett. 505:47–51. 2011. View Article : Google Scholar : PubMed/NCBI

102 

Rossignol DA and Frye RE: A review of research trends in physiological abnormalities in autism spectrum disorders: Immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry. 17:389–401. 2012. View Article : Google Scholar :

103 

Mehta SL, Kumari S, Mendelev N and Li PA: Selenium preserves mitochondrial function, stimulates mitochondrial biogenesis, and reduces infarct volume after focal cerebral ischemia. BMC Neurosci. 13:792012. View Article : Google Scholar : PubMed/NCBI

104 

Badjatia N, Seres D, Carpenter A, Schmidt JM, Lee K, Mayer SA, Claassen J, Connolly ES and Elkind MS: Free fatty acids and delayed cerebral ischemia after subarachnoid hemorrhage. Stroke. 43:691–696. 2012. View Article : Google Scholar : PubMed/NCBI

105 

Chen G, Jing CH, Liu PP, Ruan D and Wang L: Induction of autophagic cell death in the rat brain caused by iron. Am J Med Sci. 345:369–374. 2013. View Article : Google Scholar

106 

McCracken E, Valeriani V, Simpson C, Jover T, McCulloch J and Dewar D: The lipid peroxidation by-product 4-hydroxynonenal is toxic to axons and oligodendrocytes. J Cereb Blood Flow Metab. 20:1529–1536. 2000. View Article : Google Scholar : PubMed/NCBI

107 

Cui J, Holmes EH, Greene TG and Liu PK: Oxidative DNA damage precedes DNA fragmentation after experimental stroke in rat brain. FASEB J. 14:955–967. 2000.PubMed/NCBI

108 

Panov A, Dikalov S, Shalbuyeva N, Hemendinger R, Greenamyre JT and Rosenfeld J: Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice. Am J Physiol Cell Physiol. 292:C708–C718. 2007. View Article : Google Scholar

109 

Hansson MJ, Månsson R, Morota S, Uchino H, Kallur T, Sumi T, Ishii N, Shimazu M, Keep MF, Jegorov A and Elmér E: Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition. Free Radic Biol Med. 45:284–294. 2008. View Article : Google Scholar : PubMed/NCBI

110 

Opii WO, Nukala VN, Sultana R, Pandya JD, Day KM, Merchant ML, Klein JB, Sullivan PG and Butterfield DA: Proteomic identification of oxidized mitochondrial proteins following experimental traumatic brain injury. J Neurotrauma. 24:772–789. 2007. View Article : Google Scholar : PubMed/NCBI

111 

Lemasters JJ, Theruvath TP, Zhong Z and Nieminen AL: Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta. 1787:1395–1401. 2009. View Article : Google Scholar : PubMed/NCBI

112 

Rasola A, Sciacovelli M, Pantic B and Bernardi P: Signal transduction to the permeability transition pore. FEBS Lett. 584:1989–1996. 2010. View Article : Google Scholar : PubMed/NCBI

113 

Esch T, Stefano GB, Fricchione GL and Benson H: The role of stress in neurodegenerative diseases and mental disorders. Neuro Endocrinol Lett. 23:199–208. 2002.PubMed/NCBI

114 

Halliwell B: Oxidative stress and neurodegeneration: Where are we now? J Neurochem. 97:1634–1658. 2006. View Article : Google Scholar : PubMed/NCBI

115 

Tsaluchidu S, Cocchi M, Tonello L and Puri BK: Fatty acids and oxidative stress in psychiatric disorders. BMC Psychiatry. 8(Suppl 1): S52008. View Article : Google Scholar : PubMed/NCBI

116 

Masood A, Nadeem A, Mustafa SJ and O'Donnell JM: Reversal of oxidative stress-induced anxiety by inhibition of phosphodi-esterase-2 in mice. J Pharmacol Exp Ther. 326:369–379. 2008. View Article : Google Scholar : PubMed/NCBI

117 

Arranz MJ and de Leon J: Pharmacogenetics and pharmacoge-nomics of schizophrenia: A review of last decade of research. Mol Psychiatry. 12:707–747. 2007. View Article : Google Scholar : PubMed/NCBI

118 

Bouayed J, Rammal H, Younos C and Soulimani R: Positive correlation between peripheral blood granulocyte oxidative status and level of anxiety in mice. Eur J Pharmacol. 564:146–149. 2007. View Article : Google Scholar : PubMed/NCBI

119 

Bouayed J, Rammal H and Soulimani R: Oxidative stress and anxiety: Relationship and cellular pathways. Oxid Med Cell Longev. 2:63–67. 2009. View Article : Google Scholar :

120 

Marazziti D, Baroni S, Picchetti M, Landi P, Silvestri S, Vatteroni E and Catena Dell'Osso M: Psychiatric disorders and mitochondrial dysfunctions. Eur Rev Med Pharmacol Sci. 16:270–275. 2012.PubMed/NCBI

121 

Ng F, Berk M, Dean O and Bush AI: Oxidative stress in psychiatric disorders: Evidence base and therapeutic implications. Int J Neuropsychopharmacol. 11:851–876. 2008. View Article : Google Scholar : PubMed/NCBI

122 

Kunz M, Gama CS, Andreazza AC, Salvador M, Ceresér KM, Gomes FA, Belmonte-de-Abreu PS, Berk M and Kapczinski F: Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 32:167–1681. 2008. View Article : Google Scholar

123 

Wass CE and Andreazza A: The Redox Brain and Nitric Oxide: Implications for Psychiatric Illness. J Pharmacol Clin Toxicol. 1:1008–1009. 2013.

124 

Gubert C, Stertz L, Pfaffenseller B, Panizzutti BS, Rezin GT, Massuda R, Streck EL, Gama CS, Kapczinski F and Kunz M: Mitochondrial activity and oxidative stress markers in peripheral blood mononuclear cells of patients with bipolar disorder, schizophrenia, and healthy subjects. J Psychiatr Res. 47:1396–1402. 2013. View Article : Google Scholar : PubMed/NCBI

125 

Emiliani FE, Sedlak TW and Sawa A: Oxidative stress and schizophrenia: recent breakthroughs from an old story. 27:185–190. 2014.

126 

Andreazza AC, Kauer-Sant'anna M, Frey BN, Bond DJ, Kapczinski F, Young LT and Yatham LN: Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord. 111:135–144. 2008. View Article : Google Scholar : PubMed/NCBI

127 

Scola G, Kim HK, Young LT and Andreazza AC: A fresh look at complex I in microarray data: Clues to understanding disease-specific mitochondrial alterations in bipolar disorder. Biol Psychiatry. 73:e4–e5. 2013. View Article : Google Scholar

128 

Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, de Vente J, Prickaerts J, Blokland A and Koenig G: Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology. 47:1081–1092. 2004. View Article : Google Scholar : PubMed/NCBI

129 

Werner C, Raivich G, Cowen M, Strekalova T, Sillaber I, Buters JT, Spanagel R and Hofmann F: Importance of NO/cGMP signalling via cGMP-dependent protein kinase II for controlling emotionality and neurobehavioural effects of alcohol. Eur J Neurosci. 20:3498–3506. 2004. View Article : Google Scholar : PubMed/NCBI

130 

Wang X, Pinto-Duarte A, Sejnowski TJ and Behrens MM: How Nox2-containing NADPH oxidase affects cortical circuits in the NMDA receptor antagonist model of schizophrenia. Antioxid Redox Signal. 18:1444–1462. 2013. View Article : Google Scholar :

131 

Gu F, Chauhan V, Kaur K, Brown WT, LaFauci G, Wegiel J and Chauhan A: Alterations in mitochondrial DNA copy number and the activities of electron transport chain complexes and pyruvate dehydrogenase in the frontal cortex from subjects with autism. Transl Psychiatry. 3:e2992013. View Article : Google Scholar : PubMed/NCBI

132 

Ptacek R, Stefano GB, Weissenberger S, et al: ADHD and eating disorders: risks and co-Morbidities. J Neuropsychiatric Dis Treat. In press.

133 

Ming X, Brimacombe M, Malek JH, Jani N and Wagner GC: Autism spectrum disorders and identified toxic land fills: Co-occurrence across States. Environ Health Insights. 2:55–59. 2008.PubMed/NCBI

134 

Frye RE, Delatorre R, Taylor H, Slattery J, Melnyk S, Chowdhury N and James SJ: Redox metabolism abnormalities in autistic children associated with mitochondrial disease. Transl Psychiatry. 3:e2732013. View Article : Google Scholar : PubMed/NCBI

135 

Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, Frye RE and James SJ: Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry. 2:e1342012. View Article : Google Scholar : PubMed/NCBI

136 

Kulak A, Steullet P, Cabungcal JH, Werge T, Ingason A, Cuenod M and Do KQ: Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: Insights from animal models. Antioxid Redox Signal. 18:1428–1443. 2013. View Article : Google Scholar

137 

Kream RM and Stefano GB: De novo biosynthesis of morphine in animal cells: An evidence-based model. Med Sci Monit. 12:RA207–RA219. 2006.PubMed/NCBI

138 

Kream RM, Sheehan M, Cadet P, Mantione KJ, Zhu W, Casares F and Stefano GB: Persistence of evolutionary memory: Primordial six-transmembrane helical domain mu opiate receptors selectively linked to endogenous morphine signaling. Med Sci Monit. 13:SC5–SC6. 2007.PubMed/NCBI

139 

Stefano GB, Mantione KJ, Capellan L, Casares FM, Challenger S, Ramin R, Samuel JM, Snyder C and Kream RM: Morphine stimulates nitric oxide release in human mitochondria. J Bioenerg Biomembr. 47:409–417. 2015. View Article : Google Scholar : PubMed/NCBI

140 

Kream RM, Stefano GB and Rtacek R: Psychiatric implications of endogenous morphine: up-to-date review. Folia Biol (Praha). 56:231–241. 2010.

141 

Kream RM, Mantione KJ, Sheehan M and Stefano GB: Morphine's chemical messenger status in animals. Activitas Nerv Super Rediviva. 51:153–161. 2009.

142 

Mantione KJ, Cadet P, Zhu W, Kream RM, Sheehan M, Fricchione GL, Goumon Y, Esch T and Stefano GB: Endogenous morphine signaling via nitric oxide regulates the expression of CYP2D6 and COMT: Autocrine/paracrine feedback inhibition. Addict Biol. 13:118–123. 2008. View Article : Google Scholar

143 

Stefano GB, Cadet P, Kream RM and Zhu W: The presence of endogenous morphine signaling in animals. Neurochem Res. 33:1933–1939. 2008. View Article : Google Scholar : PubMed/NCBI

144 

Stefano GB, Ptacek R, Kuzelova H and Kream RM: Endogenous morphine: Up-to-date review 2011. Folia Biologica. J Cell Mol Biol. 58:49–56. 2012.

145 

Stefano GB and Scharrer B: Endogenous morphine and related opiates, a new class of chemical messengers. Adv Neuroimmunol. 4:57–67. 1994. View Article : Google Scholar : PubMed/NCBI

146 

Stefano GB: The evolvement of signal systems: Conformational matching a determining force stabilizing families of signal molecules. Comp Biochem Physiol C. 90:287–294. 1988. View Article : Google Scholar : PubMed/NCBI

147 

Stefano GB: Stereospecificity as a determining force stabilizing families of signal molecules within the context of evolution. Comparative Aspects of Neuropeptide Function. Stefano GB and Florey E: University of Manchester Press; Manchester: pp. 14–28. 1991

148 

Otten AB and Smeets HJ: Evolutionary defined role of the mitochondrial DNA in fertility, disease and ageing. Hum Reprod Update. 21:671–689. 2015. View Article : Google Scholar : PubMed/NCBI

149 

Hedges SB, Chen H, Kumar S, Wang DY, Thompson AS and Watanabe H: A genomic timescale for the origin of eukaryotes. BMC Evol Biol. 1:42001. View Article : Google Scholar : PubMed/NCBI

150 

Xavier JM, Rodrigues CM and Solá S: Mitochondria: Major Regulators of Neural Development. Neuroscientist. May 6–2015.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI

151 

Dinan TG, Stilling RM, Stanton C and Cryan JF: Collective unconscious: How gut microbes shape human behavior. J Psychiatr Res. 63:1–9. 2015. View Article : Google Scholar : PubMed/NCBI

152 

Wood JP: Communication between the minibrain in gut and enteric immune system. News Physiol Sci (NIPS). 6:64–69. 1991.

153 

Snyder C, Kream RM, Ptacek R and Stefano GB: Mitochondria, microbiome and their potential psychiatric modulation. Autism Open Access. In press.

154 

Lackner JM, Ma CX, Keefer L, Brenner DM, Gudleski GD, Satchidanand N, Firth R, Sitrin MD, Katz L, Krasner SS, et al: Type, rather than number, of mental and physical comorbidities increases the severity of symptoms in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 11:1147–1157. 2013. View Article : Google Scholar : PubMed/NCBI

155 

Guinane CM and Cotter PD: Role of the gut microbiota in health and chronic gastrointestinal disease: Understanding a hidden metabolic organ. Therap Adv Gastroenterol. 6:295–308. 2013. View Article : Google Scholar : PubMed/NCBI

156 

Peterson CT, Sharma V, Elmén L and Peterson SN: Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota. Clin Exp Immunol. 179:363–377. 2015. View Article : Google Scholar

157 

Stefano GB, Bilfinger TV and Fricchione GL: The immune-neuro-link and the macrophage: Postcardiotomy delirium, HIV-associated dementia and psychiatry. Prog Neurobiol. 42:475–488. 1994. View Article : Google Scholar : PubMed/NCBI

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March-2016
Volume 37 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Stefano GB and Stefano GB: Dysregulated mitochondrial and chloroplast bioenergetics from a translational medical perspective (Review). Int J Mol Med 37: 547-555, 2016
APA
Stefano, G.B., & Stefano, G.B. (2016). Dysregulated mitochondrial and chloroplast bioenergetics from a translational medical perspective (Review). International Journal of Molecular Medicine, 37, 547-555. https://doi.org/10.3892/ijmm.2016.2471
MLA
Stefano, G. B., Kream, R. M."Dysregulated mitochondrial and chloroplast bioenergetics from a translational medical perspective (Review)". International Journal of Molecular Medicine 37.3 (2016): 547-555.
Chicago
Stefano, G. B., Kream, R. M."Dysregulated mitochondrial and chloroplast bioenergetics from a translational medical perspective (Review)". International Journal of Molecular Medicine 37, no. 3 (2016): 547-555. https://doi.org/10.3892/ijmm.2016.2471