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CHCHD2 Regulates Mitochondrial Function and Apoptosis of Ectopic Endometrial Stromal Cells in the Pathogenesis of Endometriosis

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Abstract

Endometriosis is a disease that involves dysfunction of mitochondria, imbalance of proliferation, and apoptosis. Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is a major mitochondrial protein which could regulate the mitochondrial function and apoptosis in various tumor cells, promote migration and then lead to tumor progression. This study aimed to explore the role of CHCHD2 on endometriosis. We investigated the expression of CHCHD2 in ectopic and eutopic endometrium tissues of patients with endometriosis and normal endometrium tissues. Furthermore, CHCHD2 was downregulated to explore the corresponding change of mitochondrial function and morphology, mitochondrial-mediated apoptosis pathway, and proliferation and migration of ectopic endometrial stromal cells. Our results demonstrated that the mRNA and protein expression levels of CHCHD2 were significantly increased in eutopic and ectopic endometrium tissues compared with the normal endometrium tissues. The knockdown of CHCHD2 could cause mitochondrial dysfunction, including the opening of mitochondrial permeability transition pore, loss of mitochondrial membrane potential and the release of cytochrome c, and morphological damage. In addition, CHCHD2 down-expression could also lead to inhibition of cell proliferation, decrease of migration ability, and aggravation of mitochondrial-mediated apoptosis. Together, these findings suggest that increased expression of CHCHD2 in endometriotic tissues may contribute to the pathogenesis of endometriosis via regulating mitochondrial function and apoptosis, and CHCHD2 may be a potential target for interrupting the development of endometriosis.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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References

  1. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382(13):1244–56. https://doi.org/10.1056/nejmra1810764.

    Article  CAS  PubMed  Google Scholar 

  2. Maddern J, Grundy L, Castro J, Brierley SM. Pain in endometriosis. Front Cell Neurosci. 2020;14:590823. https://doi.org/10.3389/fncel.2020.590823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lin X, Dai Y, Tong X, Xu W, Huang Q, Jin X, et al. Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility. Redox Biol. 2020;30:101431. https://doi.org/10.1016/j.redox.2020.101431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wei Y, Liang Y, Lin H, Dai Y, Yao S. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J Neuroinflammation. 2020;17(1):80. https://doi.org/10.1186/s12974-020-01752-1.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Huijs E, Nap A. The effects of nutrients on symptoms in women with endometriosis: a systematic review. Reprod BioMed Online. 2020;41(2):317–28. https://doi.org/10.1016/j.rbmo.2020.04.014.

    Article  CAS  PubMed  Google Scholar 

  6. Tang X, Li Q, Li L, Jiang J. Expression of Talin-1 in endometriosis and its possible role in pathogenesis. Reprod Biol Endocrinol. 2021;19(1):42. https://doi.org/10.1186/s12958-021-00725-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li X, Zhang Y, Zhao L, Wang L, Wu Z, Mei Q, et al. Whole-exome sequencing of endometriosis identifies frequent alterations in genes involved in cell adhesion and chromatin-remodeling complexes. Hum Mol Genet. 2014;23(22):6008–21. https://doi.org/10.1093/hmg/ddu330.

    Article  CAS  PubMed  Google Scholar 

  8. Meng X, Liu J, Wang H, Chen P, Wang D. MicroRNA-126-5p downregulates BCAR3 expression to promote cell migration and invasion in endometriosis. Mol Cell Endocrinol. 2019;494:110486. https://doi.org/10.1016/j.mce.2019.110486.

    Article  CAS  PubMed  Google Scholar 

  9. Varma R, Rollason T, Gupta JK, Maher ER. Endometriosis and the neo-plastic process. Reproduction. 2004;127(3):293–304. https://doi.org/10.1530/rep.1.00020.

    Article  CAS  PubMed  Google Scholar 

  10. Matsuzaki S, Darcha C. Co-operation between the AKT and ERK signaling pathways may support growth of deep endometriosis in a fibrotic microenvironment in vitro. Hum Reprod. 2015;30(7):1606–16. https://doi.org/10.1093/humrep/dev108.

    Article  CAS  PubMed  Google Scholar 

  11. Govatati S, Deenadayal M, Shivaji S, Bhanoori M. Mitochondrial displacement loop alterations are associated with endometriosis. Fertil Steril. 2013; 99(7):1980–6 e9. https://doi.org/10.1016/j.fertnstert.2013.02.021

  12. Zhang Y, Tan J, Miao Y, Zhang Q. The effect of extracellular vesicles on the regulation of mitochondria under hypoxia. Cell Death Dis. 2021;12(4):358. https://doi.org/10.1038/s41419-021-03640-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wenz T. Regulation of mitochondrial biogenesis and PGC-1α under cellular stress. Mitochondrion. 2013;13(2):134–42. https://doi.org/10.1016/j.mito.2013.01.006.

    Article  CAS  PubMed  Google Scholar 

  14. Chen C, Zhou Y, Hu C, Wang Y, Yan Z, Li Z, et al. Mitochondria and oxidative stress in ovarian endometriosis. Free Radic Biol Med. 2019;136:22–34. https://doi.org/10.1016/j.freeradbiomed.2019.03.027.

    Article  CAS  PubMed  Google Scholar 

  15. Jeong SY, Seol DW. The role of mitochondria in apoptosis. BMB rep. 2008;41(1):11–22. https://doi.org/10.5483/bmbrep.2008.41.1.011.

    Article  CAS  PubMed  Google Scholar 

  16. Hajazimian S, Maleki M, Mehrabad SD, Isazadeh A. Human Wharton’s jelly stem cells inhibit endometriosis through apoptosis induction. Reproduction. 2020;159(5):549–58. https://doi.org/10.1530/rep-19-0597.

    Article  CAS  PubMed  Google Scholar 

  17. Taniguchi F, Kaponis A, Izawa M, Kiyama T, Deura I, Ito M, et al. Apoptosis and endometriosis. Front Biosci (Elite Ed). 2011;3:648–62. https://doi.org/10.2741/e277.

    Article  Google Scholar 

  18. Anderson CJ, Bredvik K, Burstein SR, Davis C, Meadows SM, Dash J, et al. ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. Acta Neuropathol. 2019;138(1):103–21. https://doi.org/10.1007/s00401-019-01989-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Modjtahedi N, Tokatlidis K, Dessen P, Kroemer G. Mitochondrial proteins containing coiled-coil-helix-coiled-coil-helix (CHCH) domains in health and disease. Trends Biochem Sci. 2016;41(3):245–60. https://doi.org/10.1016/j.tibs.2015.12.004.

    Article  CAS  PubMed  Google Scholar 

  20. Zhou ZD, Saw WT, Tan EK. Mitochondrial CHCHD-containing proteins: physiologic functions and link with neurodegenerative diseases. Mol Neurobiol. 2017;54(7):5534–46. https://doi.org/10.1007/s12035-016-0099-5.

    Article  CAS  PubMed  Google Scholar 

  21. Wei Y, Vellanki RN, Coyaud E, Ignatchenko V, Li L, Krieger JR, et al. CHCHD2 is coamplified with EGFR in NSCLC and regulates mitochondrial function and cell migration. Mol Cancer Res. 2015;13(7):1119–29. https://doi.org/10.1158/1541-7786.mcr-14-0165-t.

    Article  CAS  PubMed  Google Scholar 

  22. Song R, Yang B, Gao X, Zhang J, Sun L, Wang P, et al. Cyclic adenosine monophosphate response element-binding protein transcriptionally regulates CHCHD2 associated with the molecular pathogenesis of hepatocellular carcinoma. Mol Med Rep. 2015;11(6):4053–62. https://doi.org/10.3892/mmr.2015.3256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cheng Q, Qu D, Lu Z, Zhang L. Knockdown of CHCHD2 inhibits migration and angiogenesis of human renal cell carcinoma: a potential molecular marker for treatment of RCC. Oncol Lett. 2019;17(1):765–72. https://doi.org/10.3892/ol.2018.9686.

    Article  CAS  PubMed  Google Scholar 

  24. Ma L, Zheng LH, Zhang DG, Fan ZM. CHCHD2 decreases docetaxel sensitivity in breast cancer via activating MMP2. Eur Rev Med Pharmacol Sci. 2020; 24(11):6426–33. https://doi.org/10.26355/eurrev_202006_21541.

  25. Purandare N, Somayajulu M, Huttemann M, Grossman LI, Aras S. The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): partners in mitochondrial and nuclear function and dysfunction. J Biol Chem. 2018;293(17):6517–29. https://doi.org/10.1074/jbc.ra117.001073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Seo M, Lee WH, Suk K. Identification of novel cell migration-promoting genes by a functional genetic screen. FASEB J. 2010;24(2):464–78. https://doi.org/10.1096/fj.09-137562.

    Article  CAS  PubMed  Google Scholar 

  27. Liu Y, Zhang Y. CHCHD2 connects mitochondrial metabolism to apoptosis. Mol Cell Oncol. 2015;2(4):e1004964. https://doi.org/10.1080/23723556.2015.1004964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu H, Zhang Z, Xiong W, Zhang L, Du Y, Liu Y, et al. Long non-coding RNA MALAT1 mediates hypoxia-induced pro-survival autophagy of endometrial stromal cells in endometriosis. J Cell Mol Med. 2019;23(1):439–52. https://doi.org/10.1111/jcmm.13947.

    Article  CAS  PubMed  Google Scholar 

  29. Yin X, Xia J, Sun Y, Zhang Z. CHCHD2 is a potential prognostic factor for NSCLC and is associated with HIF-1a expression. BMC Pulm Med. 2020;20(1):40. https://doi.org/10.1186/s12890-020-1079-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Aras S, Bai M, Lee I, Springett R, Huttemann M, Grossman LI. MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. Mitochondrion. 2015;20:43–51. https://doi.org/10.1016/j.mito.2014.10.003.

    Article  CAS  PubMed  Google Scholar 

  31. Imai Y, Meng H, Shiba-Fukushima K, Hattori N. Twin CHCH proteins, CHCHD2, and CHCHD10: key molecules of Parkinson’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Int J Mol Sci. 2019;20(4):908. https://doi.org/10.3390/ijms20040908.

    Article  CAS  PubMed Central  Google Scholar 

  32. Yao Y, Su J, Zhao L, Li R, Liu K, Wang S. CHCHD2 promotes hepatocellular carcinoma and indicates poor prognosis of hepatocellular carcinoma patients. J Cancer. 2019;10(27):6822–8. https://doi.org/10.7150/jca.31158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zacksenhaus E, Shrestha M, Liu JC, Vorobieva I, Chung PED, Ju Y, et al. Mitochondrial OXPHOS induced by RB1 deficiency in breast cancer: implications for anabolic metabolism, stemness, and metastasis. Trends Cancer. 2017;3(11):768–79. https://doi.org/10.1016/j.trecan.2017.09.002.

    Article  CAS  PubMed  Google Scholar 

  34. Aras S, Maroun MC, Song Y, Bandyopadhyay S, Stark A, Yang ZQ, et al. Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis. BMC Cancer. 2019;19(1):411. https://doi.org/10.1186/s12885-019-5575-7.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Abate M, Festa A, Falco M, Lombardi A, Luce A, Grimaldi A, et al. Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin Cell Dev Biol. 2020;98:139–53. https://doi.org/10.1016/j.semcdb.2019.05.022.

    Article  CAS  PubMed  Google Scholar 

  36. Liao TL, Lee YC, Tzeng CR, Wang YP, Chang HY, Lin YF, et al. Mitochondrial translocation of estrogen receptor beta affords resistance to oxidative insult-induced apoptosis and contributes to the pathogenesis of endometriosis. Free Radic Biol Med. 2019;134:359–73. https://doi.org/10.1016/j.freeradbiomed.2019.01.022.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao Q, Ye M, Yang W, Wang M, Li M, Gu C, et al. Effect of Mst1 on endometriosis apoptosis and migration: role of Drp1-related mitochondrial fission and Parkin-required mitophagy. Cell Physiol Biochem. 2018;45(3):1172–90. https://doi.org/10.1159/000487450.

    Article  CAS  PubMed  Google Scholar 

  38. Anderson G. Endometriosis pathoetiology and pathophysiology: roles of vitamin A, estrogen, immunity, adipocytes, gut microbiome and melatonergic pathway on mitochondria regulation. Biomol Concepts. 2019;10(1):133–49. https://doi.org/10.1515/bmc-2019-0017.

    Article  CAS  PubMed  Google Scholar 

  39. Samimi M, Pourhanifeh MH, Mehdizadehkashi A, Eftekhar T, Asemi Z. The role of inflammation, oxidative stress, angiogenesis, and apoptosis in the pathophysiology of endometriosis: basic science and new insights based on gene expression. J Cell Physiol. 2019;234(11):19384–92. https://doi.org/10.1002/jcp.28666.

    Article  CAS  PubMed  Google Scholar 

  40. Ding C, Wu Z, Huang L, Wang Y, Xue J, Chen S, et al. Mitofilin and CHCHD6 physically interact with Sam50 to sustain cristae structure. Sci Rep. 2015;5:16064. https://doi.org/10.1038/srep16064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. An J, Shi J, He Q, Lui K, Liu Y, Huang Y, et al. CHCM1/CHCHD6, Novel mitochondrial protein linked to regulation of mitofilin and mitochondrial cristae morphology. J Biol Chem. 2012;287(10):7411–26. https://doi.org/10.1074/jbc.m111.277103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhou W, Ma D, Sun AX, Tran HD, Ma DL, Singh BK, et al. PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction. Hum Mol Genet. 2019;28(7):1100–16. https://doi.org/10.1093/hmg/ddy413.

    Article  CAS  PubMed  Google Scholar 

  43. Mao C, Wang H, Luo H, Zhang S, Xu H, Zhang S, et al. CHCHD10 is involved in the development of Parkinson’s disease caused by CHCHD2 loss-of-function mutation p.T61I. Neurobiol Aging. 2019;75:38–41. https://doi.org/10.1016/j.neurobiolaging.2018.10.020.

    Article  CAS  PubMed  Google Scholar 

  44. Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, et al. CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. Lancet Neurol. 2015;14(3):274–82. https://doi.org/10.1016/s1474-4422(14)70266-2.

    Article  CAS  PubMed  Google Scholar 

  45. Lin S, Schorpp K, Rothenaigner I, Hadian K. Image-based high-content screening in drug discovery. Drug Discov Today. 2020;25(8):1348–61. https://doi.org/10.1016/j.drudis.2020.06.001.

    Article  CAS  PubMed  Google Scholar 

  46. Donato M, Tolosa L. High-content screening for the detection of drug-induced oxidative stress in liver cells. Antioxidants. 2021;10(1):106. https://doi.org/10.3390/antiox10010106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Qu D, Liu C, Jiang M, Feng L, Chen Y, Han J. After in vitro digestion, jackfruit flake affords protection against acrylamide-induced oxidative damage. Molecules. 2019;24(18):3322. https://doi.org/10.3390/molecules24183322.

    Article  CAS  PubMed Central  Google Scholar 

  48. Gebel HM, Braun DP, Tambur A, Frame D, Rana N, Dmowski WP. Spontaneous apoptosis of endometrial tissue is impaired in women with endometriosis. Fertil Steril. 1998;69(6):1042–7. https://doi.org/10.1016/s0015-0282(98)00073-9.

    Article  CAS  PubMed  Google Scholar 

  49. Miyashita M, Koga K, Takamura M, Izumi G, Nagai M, Harada M, et al. Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis. Gynecol Endocrinol. 2014;30(9):644–8. https://doi.org/10.3109/09513590.2014.911279.

    Article  CAS  PubMed  Google Scholar 

  50. Tsuzuki T, Okada H, Shindoh H, Shimoi K, Nishigaki A, Kanzaki H. Effects of the hypoxia-inducible factor-1 inhibitor echinomycin on vascular endothelial growth factor production and apoptosis in human ectopic endometriotic stromal cells. Gynecol Endocrinol. 2016;32(4):323–8. https://doi.org/10.3109/09513590.2015.1121225.

    Article  CAS  PubMed  Google Scholar 

  51. Kolahdouz-Mohammadi R, Delbandi AA, Khodaverdi S, Arefi S, Arabl-ou T, Shidfar F. The effects of resveratrol treatment on Bcl-2 and Ba-x gene expression in endometriotic compared with non-endometriotic stromal cells. Iran J Public Health. 2020; 49(8):1546–54. https://doi.org/10.18502/ijph.v49i8.3900.

  52. Liu Y, Clegg HV, Leslie PL, Di J, Tollini LA, He Y, et al. CHCHD2 inhibits apoptosis by interacting with Bcl-xL to regulate Bax activation. Cell Death Differ. 2015;22(6):1035–46. https://doi.org/10.1038/cdd.2014.194.

    Article  CAS  PubMed  Google Scholar 

  53. Chen Q, Hang Y, Zhang T, Tan L, Li S, Jin Y. USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ERK pathway. Am J Physiol Cell Physiol. 2018; 315: (6)C863–72. https://doi.org/10.1152/ajpcell.00272.2018.

  54. Fu X, Yao M, Ye C, Fang T, Wu R. Osteopontin regulates endometrial stromal cell migration in endometriosis through the PI3K pathway: osteopontin regulates endometrial cell migration in endometriosis. Reprod Sci. 2021;28(2):435–46. https://doi.org/10.1007/s43032-020-00301-8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all subjects who donated the samples for this study.

Funding

This work was financially supported by the National Natural Science Foundation of China (No. 82004400), Hebei Natural Science Foundation (No. H2020423069), Projects of Department of Education of Hebei Province (No. QN2018143), and Basic Research Plan Project for Outstanding Young Teachers of Hebei University of Chinese Medicine (No. YQ2019009).

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Author notes

  1. Yanqing Ren and Xinru Wang contributed equally.

Authors and Affiliations

  1. Pharmacology Laboratory of Chinese Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050091, China

    Yanqing Ren, Xinru Wang, Jinyu Guo & Xinguo Wang

  2. Hebei TCM Formula Granule Technology Innovation Center, Shijiazhuang, 050091, China

    Yanqing Ren, Xinru Wang, Jinyu Guo & Xinguo Wang

  3. Hebei Key Laboratory of Integrative Medicine On Liver-Kidney Patterns, Institute of Integrative Medicine, Hebei University of Chinese Medicine, Qiaoxi District, No.326 Xinshi South Road, Shijiazhuang, 050091, China

    Yanqing Ren, Di Wang, Xinhua Li & Xiumei Cheng

  4. Hebei TCM Quality Evaluation & Standardization Engineering Research Center, Shijiazhuang, 050091, China

    Xinru Wang, Jinyu Guo & Xinguo Wang

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  1. Yanqing Ren
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Contributions

YQR completed the experiments and data collection and was a major contributor in writing the manuscript. XRW contributed to cell experiment and participated in the manuscript writing. JYG contributed to clinical sample collection. DW performed the immunohistochemistry and molecular biology examination of the study. XHL contributed to data collection and data analysis. XMC guided the overall design of the subject. XGW provided the laboratory for this study and reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiumei Cheng or Xinguo Wang.

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The study was approved by the Ethics Committee at the Hebei University of Chinese Medicine (No.YXLL2020006).

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Written informed consent was obtained from all subjects.

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Not applicable.

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The authors declare no competing interests.

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Ren, Y., Wang, X., Guo, J. et al. CHCHD2 Regulates Mitochondrial Function and Apoptosis of Ectopic Endometrial Stromal Cells in the Pathogenesis of Endometriosis. Reprod. Sci. 29, 2152–2164 (2022). https://doi.org/10.1007/s43032-021-00831-9

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