Hyperoxia exposure arrests alveolarization in neonatal rats via PTEN‑induced putative kinase 1‑Parkin and Nip3‑like protein X‑mediated mitophagy disorders

Yu,Xuefei; Sun,Yanli; Cai,Qing; Zhao,Xinyi; Liu,Ziyun; Xue,Xindong; Fu,Jianhua

doi:10.3892/ijmm.2020.4766

Hyperoxia exposure arrests alveolarization in neonatal rats via PTEN‑induced putative kinase 1‑Parkin and Nip3‑like protein X‑mediated mitophagy disorders

Authors:
- Xuefei Yu
- Yanli Sun
- Qing Cai
- Xinyi Zhao
- Ziyun Liu
- Xindong Xue
- Jianhua Fu
View Affiliations

Affiliations: Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: October 22, 2020 https://doi.org/10.3892/ijmm.2020.4766
Pages: 2126-2136
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is one of the most common respiratory diseases in premature new‑born humans. Mitochondria are not only the main source of reactive oxygen species but are also critical for the maintenance of homeostasis and a wide range of biological activities, such as producing energy, buffering cytosolic calcium and regulating signal transduction. However, as a critical quality control method for mitochondria, little is known about the role of mitophagy in BPD. The present study assessed mitochondrial function in hyperoxia‑exposed alveolar type II (AT‑II) cells of rats during lung development. New‑born Sprague‑Dawley rats were divided into hyperoxia (85% oxygen) and control (21% oxygen) groups. Histopathological and morphological properties of the lung tissues were assessed at postnatal days 1, 3, 7 and 14. Ultrastructural mitochondrial alteration was observed using transmission electron microscopy and the expression of the mitophagy proteins putative kinase (PINK)1, Parkin and Nip3‑like protein X (NIX) in the lung tissues was evaluated using western blotting. Immunofluorescence staining was used to determine the co‑localisation of PINK1 and Parkin. Real‑time analyses of extracellular acidification rate and oxygen consumption rate were performed using primary AT‑II cells to evaluate metabolic changes. Mitochondria in hyperoxia‑exposed rat AT‑II cells began to show abnormal morphological and physiological features. These changes were accompanied by decreased mitochondrial membrane potential and increased expression levels of PINK1‑Parkin and NIX. Increased binding between a mitochondria marker (cytochrome C oxidase subunit IV isoform I) and an autophagy marker (microtubule‑associated protein‑1 light chain‑3B) was observed in primary AT‑II cells and was accompanied by decreased mitochondrial metabolic capacity in model rats. Thus, mitophagy mediated by PINK1, Parkin and NIX in AT‑II cells occurred in hyperoxia‑exposed new‑born rats. These findings suggested that the accumulation of dysfunctional mitochondria may be a key factor in the pathogenesis of BPD and result in attenuated alveolar development.

View Figures

View References

1	Abman SH, Bancalari E and Jobe A: The evolution of bronchopulmonary dysplasia after 50 years. Am J Respir Crit Care Med. 195:421–424. 2017. View Article : Google Scholar : PubMed/NCBI
2	Surate Solaligue DE, Rodriguez-Castillo JA, Ahlbrecht K and Morty RE: Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 313:L1101–L1153. 2017. View Article : Google Scholar : PubMed/NCBI
3	Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, Hale EC, Newman NS, Schibler K, Carlo WA, et al: Neonatal outcomes of extremely preterm infants from the NICHD neonatal research network. Pediatrics. 126:443–456. 2010. View Article : Google Scholar : PubMed/NCBI
4	García-Muñoz Rodrigo F, Losada Martínez A, Elorza Fernández MD, Moreno Hernando J, Figueras Aloy J and Vento Torres M: The burden of respiratory disease in very-low-birth-weight infants: Changes in perinatal care and outcomes in a decade in Spain. Neonatology. 112:30–39. 2017. View Article : Google Scholar : PubMed/NCBI
5	Dumpa V and Bhandari V: Surfactant, steroids and non-invasive ventilation in the prevention of BPD. Semin Perinatol. 42:444–452. 2018. View Article : Google Scholar : PubMed/NCBI
6	Kalikkot Thekkeveedu R, Guaman MC and Shivanna B: Bronchopulmonary dysplasia: A review of pathogenesis and pathophysiology. Respir Med. 132:170–177. 2017. View Article : Google Scholar : PubMed/NCBI
7	Jobe AH and Abman SH: Bronchopulmonary dysplasia: A continuum of lung disease from the fetus to the adult. Am J Respir Crit Care Med. 200:659–660. 2019. View Article : Google Scholar : PubMed/NCBI
8	Chen Y, Chang L, Li W, Rong Z, Liu W, Shan R and Pan R: Thioredoxin protects fetal type II epithelial cells from hyperoxia-induced injury. Pediatr Pulmonol. 45:1192–1200. 2010. View Article : Google Scholar : PubMed/NCBI
9	McGrath-Morrow SA and Stahl J: Apoptosis in neonatal murine lung exposed to hyperoxia. Am J Respir Cell Mol Biol. 25:150–155. 2001. View Article : Google Scholar : PubMed/NCBI
10	O'Reilly MA, Staversky RJ, Finkelstein JN and Keng PC: Activation of the G2 cell cycle checkpoint enhances survival of epithelial cells exposed to hyperoxia. Am J Physiol Lung cell Mol Physiol. 284:L368–L375. 2003. View Article : Google Scholar
11	Bayne AN and Trempe JF: Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond. Cell Mol Life Sci. 76:4589–4611. 2019. View Article : Google Scholar : PubMed/NCBI
12	Wang Y, Liu N and Lu B: Mechanisms and roles of mitophagy in neurodegenerative diseases. cNS Neurosci Ther. 25:859–875. 2019.PubMed/NCBI
13	Sureshbabu A and Bhandari V: Targeting mitochondrial dysfunction in lung diseases: Emphasis on mitophagy. Front Physiol. 4:3842013. View Article : Google Scholar
14	Meissner C, Lorenz H, Weihofen A, Selkoe DJ and Lemberg MK: The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem. 117:856–867. 2011. View Article : Google Scholar : PubMed/NCBI
15	Nardin A, Schrepfer E and Ziviani E: Counteracting PINK/Parkin deficiency in the activation of mitophagy: A potential therapeutic intervention for Parkinson's disease. Curr Neuropharmacol. 14:250–259. 2016. View Article : Google Scholar :
16	Liu H, Dai C, Fan Y, Guo B, Ren K, Sun T and Wang W: From autophagy to mitophagy: The roles of P62 in neurodegenerative diseases. J Bioenerg Biomembr. 49:413–422. 2017. View Article : Google Scholar : PubMed/NCBI
17	Wei H, Liu L and Chen Q: Selective removal of mitochondria via mitophagy: Distinct pathways for different mitochondrial stresses. Biochim Biophys Acta. 1853:2784–2790. 2015. View Article : Google Scholar : PubMed/NCBI
18	Deczkowska A and Schwartz M: NIX-ing mitochondria: From development to pathology. EMBO J. 36:1650–1652. 2017. View Article : Google Scholar : PubMed/NCBI
19	Um JH and Yun J: Emerging role of mitophagy in human diseases and physiology. BMB Rep. 50:299–307. 2017. View Article : Google Scholar : PubMed/NCBI
20	Yee M, Vitiello PF, Roper JM, Staversky RJ, Wright TW, McGrath-Morrow SA, Maniscalco WM, Finkelstein JN and O'Reilly MA: Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development. Am J Physiol Lung Cell Mol Physiol. 291:L1101–L1111. 2006. View Article : Google Scholar : PubMed/NCBI
21	Cliff TS and Dalton S: Metabolic switching and cell fate decisions: Implications for pluripotency, reprogramming and development. Curr Opin Genet dev. 46:44–49. 2017. View Article : Google Scholar : PubMed/NCBI
22	Aravamudan B, Thompson MA, Pabelick CM and Prakash YS: Mitochondria in lung diseases. Expert Rev Respir Med. 7:631–646. 2013. View Article : Google Scholar : PubMed/NCBI
23	Hou A, Fu J, Yang H, Zhu Y, Pan Y, Xu S and Xue X: Hyperoxia stimulates the transdifferentiation of type II alveolar epithelial cells in newborn rats. Am J Physiol Lung Cell Mol Physiol. 308:L861–L872. 2015. View Article : Google Scholar : PubMed/NCBI
24	Hara H, Araya J, Ito S, Kobayashi K, Takasaka N, Yoshii Y, Wakui H, Kojima J, Shimizu K, Numata T, et al: Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence. Am J Physiol Lung Cell Mol Physiol. 305:L737–L746. 2013. View Article : Google Scholar : PubMed/NCBI
25	Resseguie EA, Brookes PS and O'Reilly MA: SMG-1 kinase attenuates mitochondrial ROS production but not cell respiration deficits during hyperoxia. Exp Lung Res. 43:229–239. 2017. View Article : Google Scholar : PubMed/NCBI
26	Song SB, Jang SY, Kang HT, Wei B, Jeoun UW, Yoon GS and Hwang ES: Modulation of mitochondrial membrane potential and ROS generation by nicotinamide in a manner independent of SIRT1 and mitophagy. Mol cells. 40:503–514. 2017.PubMed/NCBI
27	Peixoto P, Grandvallet C, Feugeas JP, Guittaut M and Hervouet E: Epigenetic control of autophagy in cancer cells: A key process for cancer-related phenotypes. Cells. 8:16562019. View Article : Google Scholar
28	Zachari M and Ktistakis NT: Mammalian mitophagosome formation: A focus on the early signals and steps. Front Cell Dev Biol. 8:1712020. View Article : Google Scholar : PubMed/NCBI
29	Walsh BK, Brooks TM and Grenier BM: Oxygen therapy in the neonatal care environment. Respir Care. 54:1193–1202. 2009.PubMed/NCBI
30	Jobe AH and Kallapur SG: Long term consequences of oxygen therapy in the neonatal period. Semin Fetal Neonatal Med. 15:230–235. 2010. View Article : Google Scholar : PubMed/NCBI
31	Wang J and Dong W: Oxidative stress and bronchopulmonary dysplasia. Gene. 678:177–183. 2018. View Article : Google Scholar : PubMed/NCBI
32	Bancalari E, Claure N and Sosenko IR: Bronchopulmonary dysplasia: Changes in pathogenesis, epidemiology and definition. Semin Neonatol. 8:63–71. 2003. View Article : Google Scholar : PubMed/NCBI
33	Scherz-Shouval R and Elazar Z: Regulation of autophagy by ROS: Physiology and pathology. Trends Biochem Sci. 36:30–38. 2011. View Article : Google Scholar
34	El-Merhie N, Baumgart-Vogt E, Pilatz A, Pfreimer S, Pfeiffer B, Pak O, Kosanovic D, Seimetz M, Schermuly RT, Weissmann N and Karnati S: differential alterations of the mitochondrial morphology and respiratory chain complexes during postnatal development of the mouse lung. Oxid Med Cell Longev. 2017:91691462017. View Article : Google Scholar
35	Anzell AR, Maizy R, Przyklenk K and Sanderson TH: Mitochondrial quality control and disease: Insights into ischemia-reperfusion injury. Mol Neurobiol. 55:2547–2564. 2018. View Article : Google Scholar
36	Eiyama A and Okamoto K: PINK1/Parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol. 33:95–101. 2015. View Article : Google Scholar : PubMed/NCBI
37	Ahmad T, Sundar IK, Lerner CA, Gerloff J, Tormos AM, Yao H and Rahman I: Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: Implications for chronic obstructive pulmonary disease. FASEB J. 29:2912–2929. 2015. View Article : Google Scholar : PubMed/NCBI
38	Patel AS, Song JW, Chu SG, Mizumura K, Osorio JC, Shi Y, El-chemaly S, Lee CG, Rosas IO, Elias JA, et al: Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor-beta1 in pulmonary fibrosis. PLoS One. 10:e01212462015. View Article : Google Scholar : PubMed/NCBI
39	Araya J, Tsubouchi K, Sato N, Ito S, Minagawa S, Hara H, Hosaka Y, Ichikawa A, Saito N, Kadota T, et al: PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis. Autophagy. 15:510–526. 2019. View Article : Google Scholar :
40	Zhang D, Wu L, Du Y, Zhu Y, Pan B, Xue X and Fu J: Autophagy inducers restore impaired autophagy, reduce apoptosis, and attenuate blunted alveolarization in hyperoxia-exposed newborn rats. Pediatr Pulmonol. 53:1053–1066. 2018. View Article : Google Scholar : PubMed/NCBI
41	Durcan TM and Fon EA: The three 'P's of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes dev. 29:989–999. 2015. View Article : Google Scholar : PubMed/NCBI
42	Esteban-Martinez L, Sierra-Filardi E, McGreal RS, Salazar-Roa M, Mariño G, Seco E, Durand S, Enot D, Graña O, Malumbres M, et al: Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO J. 36:1688–1706. 2017. View Article : Google Scholar : PubMed/NCBI
43	Esteban-Martinez L and Boya P: BNIP3L/NIX-dependent mitophagy regulates cell differentiation via metabolic reprogramming. Autophagy. 14:915–917. 2018. View Article : Google Scholar :
44	Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M and Wang G: The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 24:2528–2538. 2015. View Article : Google Scholar : PubMed/NCBI
45	Zhao H, Dennery PA and Yao H: Metabolic reprogramming in the pathogenesis of chronic lung diseases, including BPD, COPD, and pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 314:L544–L554. 2018. View Article : Google Scholar : PubMed/NCBI
46	Lottes RG, Newton DA, Spyropoulos DD and Baatz JE: Lactate as substrate for mitochondrial respiration in alveolar epithelial type II cells. Am J Physiol Lung cell Mol Physiol. 308:L953–L961. 2015. View Article : Google Scholar : PubMed/NCBI
47	Ratner V, Starkov A, Matsiukevich D, Polin RA and Ten VS: Mitochondrial dysfunction contributes to alveolar developmental arrest in hyperoxia-exposed mice. Am J Respir Cell Mol Biol. 40:511–518. 2009. View Article : Google Scholar : PubMed/NCBI
48	Das KC: Hyperoxia decreases glycolytic capacity, glycolytic reserve and oxidative phosphorylation in MLE-12 cells and inhibits complex I and II function, but not complex IV in isolated mouse lung mitochondria. PLoS One. 8:e733582013. View Article : Google Scholar : PubMed/NCBI
49	Simon LM, Raffin TA, Douglas WH, Theodore J and Robin ED: Effects of high oxygen exposure on bioenergetics in isolated type II pneumocytes. J Appl Physiol Respir Environ Exerc Physiol. 47:98–103. 1979.PubMed/NCBI
50	Naik PP, Birbrair A and Bhutia SK: Mitophagy-driven metabolic switch reprograms stem cell fate. cell Mol Life Sci. 76:27–43. 2019. View Article : Google Scholar
51	McCoy MK, Kaganovich A, Rudenko IN, Ding J and Cookson MR: Hexokinase activity is required for recruitment of parkin to depolarized mitochondria. Hum Mol Genet. 23:145–156. 2014. View Article : Google Scholar
52	Liu K, Li F, Han H, Chen Y, Mao Z, Luo J, Zhao Y, Zheng B, Gu W and Zhao W: Parkin regulates the activity of pyruvate kinase M2. J Biol chem. 291:10307–10317. 2016. View Article : Google Scholar : PubMed/NCBI