Extensive evidence highlights a marked increase in the prevalence of psychiatric symptoms during perimenopause (23). Epidemiological studies suggest that ~70% of women experience some form of emotional disturbance, including irritability, anxiety and depressive symptoms (24). While some women report mild mood instability, others may develop moderate-to-severe depression or anxiety that notably impairs daily functioning and social adaptation (10). A meta-analysis of 55 studies revealed a global pooled prevalence of depressive disorders in perimenopausal women at 33.9% (95% CI: 27.8-40.0%) (25). Another large population-based study involving 9,141 women revealed that perimenopausal women are at considerably higher risk of developing depressive symptoms compared with their premenopausal counterparts (26).

The onset of perimenopausal mood disorders is influenced by a complex interaction of biological and psychosocial risk factors. Low educational attainment, unemployment or part-time employment, high perceived stress, menstrual irregularity, constipation poor family relationships (27) and high neuroticism are all associated with an increased risk of depression (28). By contrast, increased household income and access to comprehensive healthcare serve as protective factors (29-32). Notably, a personal history of affective disorders predicts symptom recurrence or exacerbation during perimenopause (8,33). In women with bipolar disorder, perimenopause is often associated with a worsening of mood symptoms (29-32). One study revealed that 68% of perimenopausal women diagnosed with bipolar disorder experienced major depressive episodes, with a markedly higher frequency compared with their reproductive years (7). Similarly, longitudinal tracking of 13 women with bipolar disorder across premenopausal, perimenopausal and postmenopausal stages revealed notable mood instability during the perimenopausal transition (33).

Fluctuating decline in ovarian function during perimenopause results in considerable hormonal instability, particularly in E2 and progesterone levels. These endocrine fluctuations disrupt neurotransmitter systems and neural circuits involved in emotional regulation, leading to mood symptoms that are heterogeneous, episodic and often co-occurring with somatic and cognitive disturbances. Epidemiological studies suggest that perimenopausal women have a 2- to 4-fold increased risk of developing major depressive disorder compared with their premenopausal counterparts (34,35).

Typical depressive symptoms include persistent low mood, anhedonia, fatigue, impaired concentration, excessive guilt and pessimism regarding the future. Atypical features, such as irritability and widespread somatic complaints (such as myalgia), are also commonly reported (36). Notably, some women show reduced responsiveness to standard antidepressant therapy. The presence of severe life stress, a prior history of depression or psychotropic medication use further elevates the likelihood of progression to major depressive episodes, which may carry an increased risk of suicidal ideation and behavior (37,38).

Anxiety is another prevalent symptom cluster, often characterized by sustained tension, excessive worry, irritability and distractibility. Autonomic symptoms, such as palpitations, sweating and tremors, are frequently observed in conjunction with anxiety (39). In perimenopausal women, 60-70% report experiencing 'brain fog', a constellation of mild cognitive deficits, including forgetfulness, reduced attention and slowed thinking (40,41). While these symptoms are generally transient, persistent cognitive decline may heighten the risk for late-life neurodegenerative disorders, such as Alzheimer's disease and vascular dementia. This suggests that perimenopause may represent a key window for early intervention in cognitive aging (42).

Somatic symptoms, including hot flashes, night sweats, palpitations, headaches and musculoskeletal pain, are also common and can create a bidirectional feedback loop with mood disturbances, exacerbating both psychological and physical symptoms. Sleep disorders are highly prevalent, manifesting as difficulty falling asleep, frequent nighttime awakenings, early morning waking and non-restorative sleep (43-45). Poor sleep quality not only impairs daytime cognitive and physical functioning but is also associated with anxiety, depression and vasomotor symptoms. Notably, the interaction between vasomotor symptoms and emotional states appears to be bidirectional and temporally complex, collectively contributing to notable declines in quality of life (46,47).

Perimenopause represents a phase of profound endocrine remodeling, during which rapid and irregular fluctuations in sex hormones, particularly E2 and progesterone, markedly impact brain regions, such as the hippocampus and prefrontal cortex, involved in mood regulation (48). Several hormones, including ovarian steroids, progesterone, testosterone, cortisol and their neuroactive derivatives, have been implicated in the development and modulation of perimenopausal mood disorders (22,49).

E2 carries out a key role in this context. Following menopause, serum E2 levels reduce from premenopausal levels of 5-35 ng/dl to ~1.3 ng/dl (50,51). This sharp decline is considered a key biological event contributing to affective instability and cognitive impairment during the menopausal transition (52,53). E2 exerts neuroprotective and regulatory effects within the central nervous system (CNS). E2 deficiency induces cerebral hypoperfusion and vasoconstriction, reducing oxygen supply to brain tissue and exacerbating cognitive deficits (52). E2 receptors (ERs) α and β are widely expressed across emotion-related neural circuits, with particularly high activity in the ventral corticolimbic-brainstem axis (54,55). ERα primarily regulates nuclear gene transcription, while ERβ localizes to mitochondrial membranes, modulating mitochondrial metabolism and cellular stress responses (56).

E2 deficiency disrupts the synthesis and signaling of key neurotransmitters, such as acetylcholine, glutamate (Glu) and neuroprotective peptides, all of which are essential for cognitive function (57). Furthermore, E2 modulates dopaminergic and serotonergic systems. Its withdrawal accelerates dopaminergic neuronal degeneration, weakening reward circuitry and impairs serotonin (5-HT) synthesis and reuptake, particularly during the night, contributing to vasomotor symptoms such as hot flashes and nocturnal sweats (58,59). Dysfunctional ERβ signaling may also alter 5-HT transporter (SERT) activity and increase 5-HT₁A receptor binding in the amygdala, enhancing the processing of negative emotions and heightening vulnerability to depression and anxiety (60,61).

Progesterone levels also fluctuate considerably during perimenopause due to irregular ovulation and declining luteal function. One of its key neuroactive metabolites, allopregnanolone (ALLO), acts as a potent positive allosteric modulator of the γ-aminobutyric acid (GABA)_A receptor, enhancing inhibitory neurotransmission and exerting anxiolytic and antidepressant effects (22,62-64). However, the inconsistent synthesis of ALLO under conditions of hormonal instability may destabilize GABAergic signaling, promoting mood lability and increasing affective vulnerability (65,66). Additionally, concurrent fluctuations in ovarian hormones and neurosteroids may impair GABA_A receptor sensitivity, disrupting hypothalamic-pituitary-adrenal axis homeostasis and heightening stress responsiveness, thereby elevating susceptibility to anxiety and depressive symptoms (67,68).

Collectively, these findings emphasize the multifactorial and hormone-sensitive nature of perimenopausal mood disorders, shaped by complex interactions among E2, progesterone, neurosteroids, neurotransmitters and neuroendocrine stress systems.

Mitochondria are the primary bioenergetic organelles in eukaryotic cells, responsible for generating ATP through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) (79,80). This energy production process is driven by the electron transport chain (ETC) and ATP synthase, which together convert nutrients into usable cellular energy (81). Reducing equivalents such as NADH and flavin adenine dinucleotide (FADH₂) donate electrons to the ETC, ultimately leading to ATP synthesis and maintaining cellular homeostasis. The TCA cycle metabolizes pyruvate into carbon dioxide while producing NADH and FADH₂, which fuel the ETC (82).

Mitochondria also exhibit dynamic behavior regulated by continuous cycles of fission and fusion. These processes are key for maintaining mitochondrial integrity and function. Fission allows for the removal of damaged mitochondria and supports cellular adaptation under stress, while fusion promotes the mixing of mitochondrial contents and enhances network connectivity to optimize energy distribution (83).

In the CNS, mitochondria are key not only for sustaining neuronal energy demands but also for regulating neurotransmitter synthesis, calcium buffering, oxidative stress responses and apoptotic signaling (84) (Fig. 1). These functions are particularly vital in neurons, which have high metabolic demands. Neurons rely heavily on ATP to maintain resting membrane potential, recycle synaptic vesicles and support neurotransmitter release. Mitochondria dynamically redistribute within neurons in response to local energy needs, often clustering near synaptic terminals during periods of high activity to meet localized energy demands (85). This spatial and functional plasticity is essential for maintaining synaptic transmission, neuronal excitability and overall neurophysiological stability.

Mitochondria carry out a direct and essential role in the synthesis, metabolism and release of various neurotransmitters. Their functional integrity is important for maintaining synaptic transmission and emotional stability within the CNS (85).

Glu, the primary excitatory neurotransmitter in the brain, also serves as a precursor for the inhibitory neurotransmitter GABA (86). The synthesis of Glu is highly dependent on mitochondrial metabolism, particularly through the TCA cycle, which generates α-ketoglutarate (α-KG), a key substrate for Glu biosynthesis. Glu is then converted to GABA via Glu decarboxylase, representing a key biochemical shift from excitation to inhibition (87). In astrocytes, glutamine (Gln), the major precursor of Glu, is synthesized via Gln synthetase and transferred to neurons, where it is converted back into Glu by phosphate-activated glutaminase, further entering mitochondrial pathways.

Mitochondria function as major intracellular calcium (Ca²⁺) buffers, carrying out a key role in maintaining cytosolic calcium homeostasis (84). Calcium signaling not only facilitates intracellular signal transduction but also supports mitochondrial bioenergetics by modulating the mitochondrial membrane potential (ΔΨm), which is essential for ATP production. In the mitochondrial matrix, moderate elevations in Ca²⁺ levels activate key dehydrogenases of the TCA cycle, such as isocitrate dehydrogenase (IDH) and α-KG dehydrogenase (α-KGDH), thereby enhancing NADH production, fueling the ETC, and increasing ATP synthase activity (88).

The precise regulation of mitochondrial calcium flux is mediated by a network of transmembrane channel complexes. Under resting conditions, Ca²⁺ enters the intermembrane space through voltage-dependent anion channels located on the outer mitochondrial membrane. It then crosses the inner membrane into the matrix through the OXPHOS mitochondrial calcium uniporter (MCU) complex, which includes core subunits such as MCU, MICU1, MCUR1 and EMRE (89). These components work together to regulate Ca²⁺ uptake in a tightly controlled manner, ensuring efficient and safe calcium accumulation (90,91). During neuronal excitation, mitochondrial calcium uptake via the MCU is essential for sustaining synaptic activity. Calcium buffering within mitochondria supports synaptic vesicle fusion and neurotransmitter release by shaping local calcium transients, thereby optimizing the efficiency and timing of synaptic transmission.

In addition to their intrinsic calcium-handling systems, mitochondria are functionally and structurally connected to the ER at specialized membrane contact sites known as mitochondria-associated membranes. These microdomains facilitate calcium transfer between organelles. Upon stimulation, inositol 1,4,5-trisphosphate receptors on the ER release stored Ca²⁺ near the mitochondrial outer membrane, where it is taken up via the voltage-dependent anion channel-MCU pathway. Conversely, sarco/endoplasmic reticulum Ca²⁺-ATPase pumps recapture cytosolic Ca²⁺ back into the ER, contributing to calcium clearance and recycling (81).

Mitochondria carry out a central role in maintaining cellular redox balance, acting as both the primary source of ROS and a key platform for their detoxification and stress response. Under normal physiological conditions, electrons from NADH and FADH₂ are transferred through the mitochondrial ETC to molecular oxygen, driving ATP synthesis. However, during this process, especially at Complex I and Complex III, some electrons may prematurely reduce oxygen, generating superoxide anion (O₂^–•), the major intracellular ROS (92,93). Superoxide is rapidly dismutated by mitochondrial superoxide dismutase (SOD2) into hydrogen peroxide (H₂O₂), which can then form highly reactive hydroxyl radicals (OH•) via Fenton chemistry in the presence of transition metals such as Fe²⁺. While ROS at low levels function as signaling molecules involved in transcriptional regulation, proliferation, differentiation and immune responses (94,95), excessive ROS production can overwhelm the antioxidant defense system, leading to oxidative stress. This imbalance results in protein oxidation, lipid peroxidation, DNA damage and mitochondrial dysfunction, ultimately causing cell death or senescence (92).

The generation of ROS is further exacerbated under conditions of elevated mitochondrial membrane potential (ΔΨm) or an imbalanced NADH/NAD⁺ ratio. To mitigate this, mitochondria are equipped with robust enzymatic and non-enzymatic antioxidant systems. In addition to SOD2, enzymes such as glutathione peroxidase (GPx) and the thioredoxin-2/peroxiredoxin-3 system convert H₂O₂ into water, preventing harmful accumulation. Glutathione, a major non-enzymatic antioxidant, maintains the reduced intracellular environment and participates in free radical neutralization (96).

ROS also activate nuclear antioxidant signaling pathways that enhance cellular adaptive capacity. For example, ROS can promote the dissociation of nuclear factor erythroid 2-related factor 2 (Nrf2) from its repressor Keap1, enabling its nuclear translocation and subsequent activation of antioxidant enzyme genes, including SOD, GPx and heme oxygenase-1 (HO-1) (97). Simultaneously, ROS activate mitochondrial biogenesis and stress adaptation pathways through coactivators and transcription factors such as PGC-1α and FOXO3a, thereby enhancing mitochondrial resilience (98,99).

Moreover, mitochondrial quality control is maintained through mitophagy, a process that selectively removes damaged or ROS-overproducing mitochondria (100). This process is mediated by the PINK1/Parkin pathway: Upon collapse of the ΔΨm, PINK1 stabilizes on the outer membrane and recruits the E3 ubiquitin ligase Parkin, which tags damaged mitochondria for autophagic degradation (101). This mechanism effectively prevents the propagation of ROS-induced damage and preserves cellular homeostasis.

Mitochondria are key regulators of the dynamic balance between neuronal survival and apoptosis, serving as key checkpoints in determining cell fate. While physiological apoptosis is essential for eliminating damaged or dysfunctional neurons to maintain brain homeostasis, aberrant activation of apoptotic pathways can disrupt neural circuits and contribute to the pathogenesis of mood disorders and neurodegenerative diseases (102,103).

Under normal mitochondrial homeostasis, anti-apoptotic members of the BCL-2 family, such as BCL-2 and BCL-xL, are anchored in the outer mitochondrial membrane. These proteins inhibit apoptosis by binding to and neutralizing pro-apoptotic factors such as Bax and Bak, preventing their oligomerization and subsequent increase in mitochondrial outer membrane permeability, thereby promoting neuronal survival (104). In response to cellular stressors, including oxidative damage, calcium overload or DNA damage, pro-apoptotic pathways are activated. For instance, signaling through the Bad/p53 complex or the JNK-Bim axis promotes the conformational activation and translocation of Bax to the mitochondrial outer membrane. This destabilizes the membrane, leading to a decrease in ΔΨm and the opening of the mitochondrial permeability transition pore (mPTP) (105). Upon mPTP opening, cytochrome c (Cyt c) is released from the mitochondrial intermembrane space into the cytosol, initiating the intrinsic (mitochondrial) apoptotic pathway. In the cytoplasm, Cyt c binds to apoptotic protease-activating factor-1 and procaspase-9, forming the apoptosome. This multiprotein complex activates executioner caspases, such as caspase-3, initiating a cascade of proteolytic events that ultimately lead to the programmed death and clearance of damaged neurons (106).

E2 regulates mitochondrial function through both classical nuclear receptor signaling and rapid non-genomic pathways, collectively coordinating mitochondrial biogenesis, morphology, metabolic activity and responses to cellular stress (Fig. 2) (107).

At the transcriptional level, E2 binds to its receptor isoforms, ERα and ERβ, to activate several nuclear-encoded mitochondrial regulatory factors, including nuclear respiratory factor 1 (NRF1) and PGC-1α (107,108). NRF1 and PGC-1α work synergistically to promote the expression of key genes such as mitochondrial transcription factor A (TFAM), which facilitates mtDNA transcription, replication and translation, thus supporting the structural and functional integrity of OXPHOS complexes (109-111). Notably, ERβ is also localized to the mitochondrial membrane, where it exerts direct non-genomic control over mitochondrial respiration (112,113). By modulating Cyt c oxidase (complex IV) activity and stabilizing Δψm, ERβ enhances respiratory efficiency and reduces electron leakage (113).

E2 further upregulates key mitochondrial antioxidant enzymes, including SOD2, GPx and catalase, thereby enhancing ROS-scavenging capacity (109). It may also indirectly reduce ROS production by increasing Cyt c mRNA and protein expression, thereby strengthening antioxidant defenses (114). Beyond metabolic and redox control, E2 influences mitochondrial morphology by suppressing the recruitment and activation of the fission-related protein dynamin-related protein 1 (Drp1) and promoting the expression of fusion proteins such as mitofusin 1/2 (Mfn1/2) and optic atrophy 1 (OPA1) (115). These actions together support mitochondrial network integrity and ensure efficient energy distribution (116).

During menopause, the abrupt decline in E2 has been revealed to disrupt mitochondrial homeostasis, leaving measurable bioenergetic signatures across both central and peripheral tissues (99,107-112,114-117) (Table I). Clinical studies indicate that postmenopausal women exhibit a ~30% reduction in ATP production efficiency, which associates directly with decreased activity of mitochondrial complex IV, COX (118). Translational neuroimaging studies, combining ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) and phosphorus-31 magnetic resonance spectroscopy (³¹P-MRS), reveal a concurrent decline in cerebral metabolic rate of glucose consumption (CMRglc) and OXPHOS efficiency in perimenopausal women (118). Notably, the extent of metabolic decline is inversely correlated with Beck Depression Inventory-II (BDI-II) scores, suggesting an association between impaired brain energetics and depressive symptom severity (119). Furthermore, reduced glucose utilization in the brain has been associated with decreased Cyt c oxidase activity in peripheral blood platelets, indicating a parallel dysfunction of mitochondrial metabolism in both the CNS and peripheral tissues (120). This pattern of metabolic disruption appears to result not merely from chronological aging, but from hormone-driven 'endocrine aging' that destabilizes mitochondrial function. Collectively, these findings highlight mitochondrial E2 dependence as a key mechanistic factor underlying perimenopausal mood disorders.

E2 deficiency during perimenopause is a major driver of mitochondrial bioenergetic impairment, with the ETC being a primary target. Experimental studies indicate that E2 enhances the expression and activity of several ETC complexes, including Complex I (NDUFB8), Complex IV (MTCO1) and Complex V (121). In the absence of E2, the Erβ-PGC-1α-NRF1 transcriptional axis is downregulated, leading to reduced expression of OXPHOS subunits, decreased ΔΨm and impaired coupling between substrate oxidation and ATP synthesis (122). In ovariectomized rats, mitochondrial oxygen consumption rate in skeletal muscle decreases by ~25% at rest, with maximal respiratory capacity reduced by up to ≤40% (123). These deficits associate with diminished expression of Complex I and IV subunits, highlighting the structural and functional deterioration of the ETC as a key mechanism underlying energy failure due to E2 deficiency.

Additionally, E2 regulates the TCA cycle through epigenetic mechanisms. E2 withdrawal suppresses sirtuin 1-mediated deacetylation of key metabolic enzymes, resulting in downregulation of IDH 3α (IDH3α) and α-KGDH, both rate-limiting enzymes in the TCA cycle (124,125). This suppression limits NADH production, reducing electron supply to the ETC and slowing TCA cycle throughput.

E2 also positively regulates the expression and assembly of the MCU complex. When E2 levels decline <50 pg/ml, dysfunctional MCU assembly limits mitochondrial Ca²⁺ uptake, impairing ATP synthase activation and disrupting calcium-dependent apoptotic signaling (126). Mitochondrial Ca²⁺ is essential for activating key dehydrogenases in the TCA cycle, such as pyruvate dehydrogenase (PDH), IDH and α-KGDH, which facilitate NADH and FADH₂ production. These reducing equivalents fuel the ETC, enhancing ATP synthesis and supporting mitochondrial bioenergetics. In perimenopausal women, E2 deficiency reduces mitochondrial Ca²⁺ sensitivity, impairing respiratory efficiency and energy output (127). Moreover, dysregulated mitochondrial Ca²⁺ buffering disrupts the spatial and temporal precision of calcium transients required for synaptic vesicle release. This leads to inefficient neurotransmission and contributes to excitatory/inhibitory (E/I) imbalance, often manifested as elevated extracellular Glu levels and reduced GABAergic tone. Such imbalances compromise synaptic plasticity, long-term potentiation and network stability in limbic regions (128).

Furthermore, E2 deficiency impairs fatty acid oxidation by downregulating carnitine palmitoyltransferase I, a key enzyme responsible for mitochondrial fatty acid uptake and β-oxidation. This defect limits the utilization of alternative energy substrates and reduces overall metabolic flexibility (125). E2 also influences glucose metabolism at multiple regulatory points. Its absence leads to reduced expression of glucose transporters GLUT1 and GLUT4 in the brain, and GLUT3 and GLUT4 in peripheral tissues. Additionally, increased phosphorylation of PDH inhibits its activity, impairing pyruvate utilization and mitochondrial entry. These combined effects result in reduced glucose uptake and decreased lactate production, reflecting a broad suppression of glucose oxidative capacity (129).

E2 deficiency markedly disrupts mitochondrial antioxidant defense systems, exacerbating oxidative stress and contributing to mitochondrial dysfunction. The phenolic hydroxyl group of E2, particularly on the A-ring, acts as a direct free radical scavenger by donating hydrogen atoms to neutralize ROS, thereby exerting non-enzymatic antioxidant effects (118). In perimenopausal women, a decline in circulating E2 levels is associated with a 50-80% increase in ROS production, positioning E2 loss as a key driver of mitochondrial oxidative stress. E2 deficiency downregulates the Erβ-PGC-1α-NRF1 transcriptional axis, leading to suppressed SOD2 expression and impaired clearance of mitochondrial ROS, initiating a vicious cycle of oxidative damage and mitochondrial destabilization (122). Concurrently, reduced expression of OXPHOS subunits further impairs mitochondrial electron flow, resulting in decreased ΔΨm and diminished coupling efficiency. These alterations increase the NADH/NAD⁺ ratio, which inhibits Complex I activity and promotes electron leakage to oxygen, generating additional superoxide radicals and intensifying oxidative injury (130).

Excessive ROS not only impair ETC function but also activate pro-inflammatory and pro-apoptotic pathways. For example, elevated ROS levels can trigger the assembly of NLRP3 inflammasomes, promote mPTP opening and initiate caspase-mediated apoptosis. These downstream effects contribute to neuroinflammation and neuronal loss, thereby reinforcing the pathological association between E2 decline, mitochondrial dysfunction and mood disorders during perimenopause (131).

E2 decline also promotes mitochondrial fission, resulting in fragmented mitochondria with disorganized cristae and reduced inter-organelle connectivity. Such fragmentation impairs substrate and protein exchange across the mitochondrial network, compromises ΔΨm and reduces coupling efficiency between electron transport and ATP synthesis.

Mechanistically, E2 deficiency increases the expression and activation of the fission protein Drp1, particularly through phosphorylation at Ser616. By contrast, the expression of key fusion proteins, Mfn1/2 and Opa1, is downregulated (117). This imbalance between enhanced fission and suppressed fusion leads to structural fragmentation, metabolic uncoupling and deterioration of respiratory chain function, all of which contribute to bioenergetic failure.

To illustrate the association between E2 signaling, mitochondrial integrity and mood regulation, a conceptual framework outlining the hormone-mitochondria-mood axis is proposed (Fig. 3). As summarized, declining E2 levels during perimenopause disrupt key mitochondrial processes, such as biogenesis, antioxidant defense, calcium homeostasis, mitophagy and energy metabolism, through multiple nuclear and cytoplasmic signaling pathways (132). These impairments collectively compromise neuronal function and synaptic plasticity in emotion-related brain regions, such as the hippocampus and prefrontal cortex, contributing to the onset of affective and cognitive symptoms (133).