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Chemical inhibition of mitochondrial fission improves insulin signaling and subdues hyperglycemia induced stress in placental trophoblast cells

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Abstract

Background

Gestational diabetes mellitus (GDM) is a metabolic complication that affects millions of pregnant women in the world. Placental tissue function is endangered by hyperglycemia during GDM, which is correlated to increased incidences of pregnancy complications. Recently we showed that due to a significant decrease in mitochondrial fusion, mitochondrial dynamics equilibrium is altered in placental tissues from GDM patients. Evidence for the role of reduced mitochondrial fusion in the disruption of mitochondrial function in placental cells is limited.

Methods and Results

Here we show that chemical inhibition of mitochondrial fission in cultured placental trophoblast cells leads to an increase in mitochondrial fusion and improves the physiological state of these cells and hence, their capacity to cope in a hyperglycemic environment. Specifically, mitochondrial fission inhibition led to a reduction in reactive oxygen species (ROS) generation, mitochondrial unfolded protein marker expressions, and mitochondrial depolarization. It supported the increase in mitochondrial antioxidant enzyme expressions as well. Mitochondrial fission inhibition also increases the placental cell insulin sensitivity during hyperglycemia.

Conclusion

Our results suggest that mitochondrial fusion/fission equilibrium is critical for placental cell function and signify the therapeutic potential of small molecule inhibitors of fission during GDM.

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References

  1. Association AD (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Supplement 1):S81–S90

    Article  Google Scholar 

  2. Neiger R (2017) Long-term effects of pregnancy complications on maternal health: a review. J Clin Med 6(8):76

    Article  Google Scholar 

  3. Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, Roumain J, Bennett PH, Knowler WC (2000) Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 49(12):2208–2211

    Article  CAS  Google Scholar 

  4. Langer O, Yogev Y, Most O, Xenakis EM (2005) Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol 192(4):989–997

    Article  Google Scholar 

  5. Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J (2003) Gestational diabetes and insulin resistance: role in short-and long-term implications for mother and fetus. J Nutr 133(5):1674S–1683S

    Article  CAS  Google Scholar 

  6. López-Tello J, Pérez-García V, Khaira J, Kusinski LC, Cooper WN, Andreani A, Grant I, de Liger EF, Lam BY, Hemberger M (2019) Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus in mice. Elife 8:e45282

    Article  Google Scholar 

  7. Sandovici I, Hoelle K, Angiolini E, Constância M (2012) Placental adaptations to the maternal–fetal environment: implications for fetal growth and developmental programming. Reprod Biomed Online 25(1):68–89

    Article  Google Scholar 

  8. Desforges M, Sibley CP (2009) Placental nutrient supply and fetal growth. Int J Dev Biol 54(2–3):377–390

    Google Scholar 

  9. Burton GJ, Yung HW, Murray AJ (2017) Mitochondrial–endoplasmic reticulum interactions in the trophoblast: stress and senescence. Placenta 52:146–155

    Article  CAS  Google Scholar 

  10. Martinez F, Olvera-Sanchez S, Esparza-Perusquia M, Gomez-Chang E, Flores-Herrera O (2015) Multiple functions of syncytiotrophoblast mitochondria. Steroids 103:11–22

    Article  CAS  Google Scholar 

  11. Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11(12):872–884

    Article  CAS  Google Scholar 

  12. Youle RJ, Van Der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337(6098):1062–1065

    Article  CAS  Google Scholar 

  13. Galloway CA, Yoon Y (2013) Mitochondrial morphology in metabolic diseases. Antioxid Redox Sign 19(4):415–430

    Article  CAS  Google Scholar 

  14. Otera H, Mihara K (2011) Molecular mechanisms and physiologic functions of mitochondrial dynamics. J Biochem 149(3):241–251

    Article  CAS  Google Scholar 

  15. Yoon Y, Galloway CA, Jhun BS, Yu T (2011) Mitochondrial dynamics in diabetes. Antioxid Redox Sign 14(3):439–457

    Article  CAS  Google Scholar 

  16. Gerber PA, Rutter GA (2017) The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Sign 26(10):501–518

    Article  CAS  Google Scholar 

  17. Wu G, Xiong Q, Wei X, Wang Y, Hu X, He G, Liu L, Lai Q, Dai Z, Anushesh D (2019) Mitochondrial unfolded protein response gene CLPP changes mitochondrial dynamics and affects mitochondrial function. PeerJ 7:e7209

    Article  Google Scholar 

  18. Wang L, Ishihara T, Ibayashi Y, Tatsushima K, Setoyama D, Hanada Y, Takeichi Y, Sakamoto S, Yokota S, Mihara K (2015) Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. Diabetologia 58(10):2371–2380

    Article  CAS  Google Scholar 

  19. Lin H-Y, Weng S-W, Chang Y-H, Su Y-J, Chang C-M, Tsai C-J, Shen F-C, Chuang J-H, Lin T-K, Liou C-W (2018) The causal role of mitochondrial dynamics in regulating insulin resistance in diabetes: link through mitochondrial reactive oxygen species. Oxidative Medicine and Cellular Longevity 2018

  20. Hulme CH, Nicolaou A, Murphy SA, Heazell AE, Myers JE, Westwood M (2019) The effect of high glucose on lipid metabolism in the human placenta. Sci Rep 9(1):1–9

    Article  CAS  Google Scholar 

  21. Hulme C, Stevens A, Dunn W, Heazell AE, Hollywood K, Begley P, Westwood M, Myers J (2018) Identification of the functional pathways altered by placental cell exposure to high glucose: lessons from the transcript and metabolite interactome. Sci Rep 8(1):1–11

    Article  CAS  Google Scholar 

  22. He M-y, Wang G, Han S-s, Jin Y, Li H, Wu X, Ma Z-l, Cheng X, Tang X, Yang X (2016) Nrf2 signalling and autophagy are involved in diabetes mellitus-induced defects in the development of mouse placenta. Open biology 6(7):160064

    Article  Google Scholar 

  23. Wada J, Nakatsuka A (2016) Mitochondrial dynamics and mitochondrial dysfunction in diabetes. Acta Med Okayama 70(3):151–158

    CAS  Google Scholar 

  24. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14(2):193–204

    Article  CAS  Google Scholar 

  25. Wang Q, Zhang M, Torres G, Wu S, Ouyang C, Xie Z, Zou M-H (2017) Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes 66(1):193–205

    Article  CAS  Google Scholar 

  26. Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10(6):839–850

    Article  CAS  Google Scholar 

  27. Gao D, Zhang L, Dhillon R, Hong T-T, Shaw RM, Zhu J (2013) Dynasore protects mitochondria and improves cardiac lusitropy in Langendorff perfused mouse heart.PLoS One8 (4)

  28. Qi X, Qvit N, Su Y-C, Mochly-Rosen D (2013) A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci 126(3):789–802

    CAS  Google Scholar 

  29. Su Y-C, Qi X (2013) Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet 22(22):4545–4561

    Article  CAS  Google Scholar 

  30. Zhan L, Cao H, Wang G, Lyu Y, Sun X, An J, Wu Z, Huang Q, Liu B, Xing J (2016) Drp1-mediated mitochondrial fission promotes cell proliferation through crosstalk of p53 and NF-κB pathways in hepatocellular carcinoma. Oncotarget 7(40):65001

    Article  Google Scholar 

  31. Kolac UK, Eken MK, Ünübol M, Yalcin GD, Yalcin A (2021) The effect of gestational diabetes on the expression of mitochondrial fusion proteins in placental tissue. Placenta 115:106–114

    Article  CAS  Google Scholar 

  32. Easton ZJ, Luo X, Li L, Regnault TR (2022) The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis. bioRxiv

  33. Inadera H, Tachibana S, Takasaki I, Tatematsu M, Shimomura A (2010) Hyperglycemia perturbs biochemical networks in human trophoblast BeWo cells. Endocr J 57(7):567–577

    Article  CAS  Google Scholar 

  34. Yalcin A, Şarkici G, Kolaç UK (2020) PKR inhibitors suppress endoplasmic reticulum stress and subdue glucolipotoxicitymediated impairment of insulin secretion in pancreatic beta cells. Turkish J Biology 44(2):93–102

    Article  CAS  Google Scholar 

  35. Bordt EA, Clerc P, Roelofs BA, Saladino AJ, Tretter L, Adam-Vizi V, Cherok E, Khalil A, Yadava N, Shealinna XG (2017) The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species. Dev Cell 40(6):583–594 e586

    Article  CAS  Google Scholar 

  36. Wappler EA, Institoris A, Dutta S, Katakam PV, Busija DW (2013) Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures.PloS one8 (5)

  37. Chung C-L, Sheu J-R, Liu H-E, Chang S-C, Chou Y-C, Chen W-L, Chou D-S, Hsiao G (2009) Dynasore, a dynamin inhibitor, induces PAI-1 expression in MeT-5A human pleural mesothelial cells. Am J Respir Cell Mol Biol 40(6):692–700

    Article  CAS  Google Scholar 

  38. Girard E, Paul JL, Fournier N, Beaune P, Johannes L, Lamaze C, Védie B (2011) The dynamin chemical inhibitor dynasore impairs cholesterol trafficking and sterol-sensitive genes transcription in human HeLa cells and macrophages. PloS one 6 (12)

  39. Joshi AU, Saw NL, Vogel H, Cunnigham AD, Shamloo M, Mochly-Rosen D (2018) Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis.EMBO molecular medicine10 (3)

  40. Kumari S, Anderson L, Farmer S, Mehta SL, Li PA (2012) Hyperglycemia alters mitochondrial fission and fusion proteins in mice subjected to cerebral ischemia and reperfusion. Translational stroke research 3(2):296–304

    Article  CAS  Google Scholar 

  41. Yu T, Sheu S-S, Robotham JL, Yoon Y (2008) Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovascular Res 79(2):341–351

    Article  CAS  Google Scholar 

  42. Xu Z, Zhang L, Li X, Jiang Z, Sun L, Zhao G, Zhou G, Zhang H, Shang J, Wang T (2015) Mitochondrial fusion/fission process involved in the improvement of catalpol on high glucose-induced hepatic mitochondrial dysfunction. Acta Biochim Biophys Sin 47(9):730–740

    Article  CAS  Google Scholar 

  43. Cerqueira FM, Chausse B, Baranovski BM, Liesa M, Lewis EC, Shirihai OS, Kowaltowski AJ (2016) Diluted serum from calorie-restricted animals promotes mitochondrial β‐cell adaptations and protect against glucolipotoxicity. FEBS J 283(5):822–833

    Article  CAS  Google Scholar 

  44. Shenouda SM, Widlansky ME, Chen K, Xu G, Holbrook M, Tabit CE, Hamburg NM, Frame AA, Caiano TL, Kluge MA (2011) Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation 124(4):444–453

    Article  CAS  Google Scholar 

  45. Brown GC, Murphy MP, Jornayvaz FR, Shulman GI (2010) Regulation of mitochondrial biogenesis. Essays Biochem 47:69–84

    Article  Google Scholar 

  46. Guo C, Wang J, Jing L, Ma R, Liu X, Gao L, Cao L, Duan J, Zhou X, Li Y (2018) Mitochondrial dysfunction, perturbations of mitochondrial dynamics and biogenesis involved in endothelial injury induced by silica nanoparticles. Environ Pollut 236:926–936

    Article  CAS  Google Scholar 

  47. Kiritoshi S, Nishikawa T, Sonoda K, Kukidome D, Senokuchi T, Matsuo T, Matsumura T, Tokunaga H, Brownlee M, Araki E (2003) Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. Diabetes 52(10):2570–2577

    Article  CAS  Google Scholar 

  48. Nishikawa T, Edelstein D, Du XL, Yamagishi S-i, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes H-P (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779):787–790

    Article  CAS  Google Scholar 

  49. Sivitz WI, Yorek MA (2010) Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Sign 12(4):537–577

    Article  CAS  Google Scholar 

  50. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin C-T, Price JW, Kang L, Rabinovitch PS, Szeto HH (2009) Mitochondrial H 2 O 2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 119(3):573–581

    Article  CAS  Google Scholar 

  51. Yu T, Robotham JL, Yoon Y (2006) Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proceedings of the National Academy of Sciences 103 (8):2653–2658

  52. Haynes CM, Fiorese CJ, Lin Y-F (2013) Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond. Trends Cell Biol 23(7):311–318

    Article  CAS  Google Scholar 

  53. Deepa SS, Bhaskaran S, Ranjit R, Qaisar R, Nair BC, Liu Y, Walsh ME, Fok WC, Van Remmen H (2016) Down-regulation of the mitochondrial matrix peptidase ClpP in muscle cells causes mitochondrial dysfunction and decreases cell proliferation. Free Radical Bio Med 91:281–292

    Article  CAS  Google Scholar 

  54. Becker C, Kukat A, Szczepanowska K, Hermans S, Senft K, Brandscheid CP, Maiti P, Trifunovic A (2018) CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis. EMBO Rep 19(5):e45126

    Article  Google Scholar 

  55. Hall L, Martinus RD (2013) Hyperglycaemia and oxidative stress upregulate HSP60 & HSP70 expression in HeLa cells. Springerplus 2(1):1–10

    Article  Google Scholar 

  56. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1(4):515–525

    Article  CAS  Google Scholar 

  57. Clerc P, Ge S, Hwang H, Waddell J, Roelofs B, Karbowski M, Sesaki H, Polster B (2014) Drp 1 is dispensable for apoptotic cytochrome c release in primed MCF 10 A and fibroblast cells but affects Bcl-2 antagonist‐induced respiratory changes. Br J Pharmacol 171(8):1988–1999

    Article  CAS  Google Scholar 

  58. Sugioka R, Shimizu S, Tsujimoto Y (2004) Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem 279(50):52726–52734

    Article  CAS  Google Scholar 

  59. Holland O, Nitert MD, Gallo LA, Vejzovic M, Fisher JJ, Perkins AV (2017) Placental mitochondrial function and structure in gestational disorders. Placenta 54:2–9

    Article  CAS  Google Scholar 

  60. Jheng H-F, Tsai P-J, Guo S-M, Kuo L-H, Chang C-S, Su I-J, Chang C-R, Tsai Y-S (2012) Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol 32(2):309–319

    Article  CAS  Google Scholar 

  61. Chan DC (2012) Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet 46:265–287

    Article  CAS  Google Scholar 

  62. Liesa M, Shirihai OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metabol 17(4):491–506

    Article  CAS  Google Scholar 

  63. Hastie R, Lappas M (2014) The effect of pre-existing maternal obesity and diabetes on placental mitochondrial content and electron transport chain activity. Placenta 35(9):673–683

    Article  CAS  Google Scholar 

  64. Fisher JJ, Vanderpeet CL, Bartho LA, McKeating DR, Cuffe JS, Holland OJ, Perkins AV (2021) Mitochondrial dysfunction in placental trophoblast cells experiencing gestational diabetes mellitus. J Physiol 599(4):1291–1305

    Article  CAS  Google Scholar 

  65. Prasun P (2020) Mitochondrial dysfunction in metabolic syndrome. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 1866:16583810

  66. Das M, Sauceda C, Webster NJ (2021) Mitochondrial dysfunction in obesity and reproduction. Endocrinology 162(1):bqaa158

    Article  Google Scholar 

  67. Wang J, Lin X, Zhao N, Dong G, Wu W, Huang K, Fu J (2022) Effects of Mitochondrial Dynamics in the Pathophysiology of Obesity. Front Bioscience-Landmark 27(3):107

    Article  CAS  Google Scholar 

  68. Mandò C, Anelli GM, Novielli C, Panina-Bordignon P, Massari M, Mazzocco MI, Cetin I (2018) Impact of obesity and hyperglycemia on placental mitochondria. Oxidative medicine and cellular longevity 2018

  69. Wu B, Chen Y, Clarke R, Akala E, Yang P, He B, Gao H (2022) AMPK Signaling Regulates Mitophagy and Mitochondrial ATP Production in Human Trophoblast Cell Line BeWo. Front Bioscience-Landmark 27(4):118

    Article  CAS  Google Scholar 

  70. Wasilewski M, Semenzato M, Rafelski SM, Robbins J, Bakardjiev AI, Scorrano L (2012) Optic atrophy 1-dependent mitochondrial remodeling controls steroidogenesis in trophoblasts. Curr Biol 22(13):1228–1234

    Article  CAS  Google Scholar 

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Funding

This research was supported by the Scientific and Technological Research Council of Turkey (TUBİTAK Project No: 120S283).

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  1. Department of Medical Biology, Faculty of Medicine, Aydin Adnan Menderes University, 09010, Efeler, Aydin, Turkey

    Umut Kerem Kolac, Gizem Donmez Yalcin & Abdullah Yalcin

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  1. Umut Kerem Kolac
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  2. Gizem Donmez Yalcin
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  3. Abdullah Yalcin
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Contributions

U.K.K. design and conduction of the research, analysis and interpretation of the data and writing of the initial draft of the manuscript. A.Y. and G.D.Y. analysis and interpretation of the data and writing of the initial draft of the manuscript. All the authors have read and agreed to the final version of the manuscript.

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Correspondence to Abdullah Yalcin.

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Kolac, U.K., Donmez Yalcin, G. & Yalcin, A. Chemical inhibition of mitochondrial fission improves insulin signaling and subdues hyperglycemia induced stress in placental trophoblast cells. Mol Biol Rep 50, 493–506 (2023). https://doi.org/10.1007/s11033-022-07959-0

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