MitoTEMPOL modulates mitophagy and histopathology of Wistar rat liver after streptozotocin injection

Document Type : Original Article

Authors

1 Department of Ophthalmology, Universitas Padjadjaran, Bandung, West Java, Indonesia

2 Cicendo National Eye Hospital, Bandung, West Java, Indonesia

3 Department of Physiology, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia

4 Biology Cell Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia

5 Department of Internal Medicine, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia

6 Department of Pharmacology, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia

7 Department of Pathology Anatomy, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia

8 Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia

9 Physiology Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia

10 Physiology Molecular Laboratory, Biological Activity Division, Central Laboratory, Universitas Padjadjaran, Jatinangor, West Java, Indonesia

Abstract

Objective(s): This study aims to explore the effect of mitoTEMPOL on histopathology, lipid droplet, and mitophagy gene expression of Wistar rat’s liver after injection of streptozotocin (STZ).
Materials and Methods: Twenty male Wistar rats were divided into 4 groups: Control (n=5); 100 mg/kg BW/day mitoTEMPOL orally (n=5); 50 mg/kg BW STZ intraperitoneal injection (n=5); and mitoTEMPOL+STZ (n=5). STZ was given a single dose, while mitoTEMPOL was given for 5 weeks after 1 week of STZ injection. Histopathological appearance, lipid droplets, mitophagy, and autophagy gene expression were examined after the mitoTEMPOL treatment. 
Results: We found metabolic zone shifting that might be correlated with the liver activity of fatty acid oxidation in the STZ group, a decrease of lipid droplets in mitoTEMPOL and mitoTEMPOL + STZ compared with Control and STZ groups were found in this study. We also found significant changes in PINK1, Parkin, BNIP3, Mfn1, and LC3 gene expression, but no difference in Opa1, Fis1, Drp1, and p62 gene expression, suggesting a change of mitochondrial fusion rather than mitochondrial fission correlated with mitophagy.
Conclusion: All this concluded that mitoTEMPOL could act as a modulator of mitophagy and metabolic function of the liver, thus amplifying its crucial role in preventing mitochondrial damage in the liver in the early onset of diabetes mellitus.

Keywords

References

1. Papatheodorou K, Banach M, Bekiari E, Rizzo M, Edmonds M. Complications of diabetes 2017. J Diabetes Res 2018; 2018: 3086167. 
2. Kobayashi S, Zhao F, Zhang Z, Kobayashi T, Huang Y, Shi B, et al. Mitochondrial fission and mitophagy coordinately restrict high glucose toxicity in  cardiomyocytes. Front Physiol 2020;11:604069. 
3. Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 2016;65:1049–1061. 
4. Wu J, Yan L-J. Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity. Diabetes Metab Syndr Obes 2015;8:181-188. 
5. Ghasemi A, Khalifi S, Jedi S. Streptozotocin-nicotinamide-induced rat model of type 2 diabetes (review). Acta Physiol Hung 2014;101:408–420. 
6. Deeds MC, Anderson JM, Armstrong AS, Gastineau DA, Hiddinga HJ, Jahangir A, et al. Single dose streptozotocin-induced diabetes: considerations for study design in  islet transplantation models. Lab Anim 2011;45:131-140. 
7. Johansson EB, Tjalve H. Studies on the tissue-disposition and fate of [14C]streptozotocin with special  reference to the pancreatic islets. Acta Endocrinol (Copenh) 1978;89:339–351. 
8. Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 2008;51:216–226. 
9. Tesch GH, Allen TJ. Rodent models of streptozotocin-induced diabetic nephropathy. Nephrology (Carlton) 2007;12:261–266. 
10. Rolfe DF, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in  mammals. Physiol Rev 1997;77:731–758. 
11. Shum M, Ngo J, Shirihai OS, Liesa M. Mitochondrial oxidative function in NAFLD: Friend or foe? Mol Metab 2021;50:101134. 
12. Kim J-A, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res. 2008;102:401-414. 
13. Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders-A step towards mitochondria based therapeutic strategies. Biochim Biophys acta Mol basis Dis 2017;1863:1066–1077. 
14. Yan L-J. Pathogenesis of chronic hyperglycemia: From reductive stress to oxidative stress. J Diabetes Res 2014;2014:137919. 
15. Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother 2018;107:306-228. 
16. Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 2007;83:84-92. 
17. Belousov DM, Mikhaylenko E V, Somasundaram SG, Kirkland CE, Aliev G. The dawn of mitophagy: What do we know by now? Curr Neuropharmacol 2021;19:170-192. 
18. Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol 2018;28:170–185. 
19. Yuan Y, Zheng Y, Zhang X, Chen Y, Wu X, Wu J, et al. BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of  PARK2. Autophagy 2017;13:1754–1766. 
20. Li Y, Liu Z, Zhang Y, Zhao Q, Wang X, Lu P, et al. PEDF protects cardiomyocytes by promoting FUNDC1‑mediated mitophagy via PEDF-R under  hypoxic condition. Int J Mol Med 2018;41:3394-3404. 
21. Sato S, Furuya N. Induction of PINK1/Parkin-Mediated Mitophagy. Methods Mol Biol 2018;1759:9–17. 
22. Su Z, Nie Y, Huang X, Zhu Y, Feng B, Tang L, et al. Mitophagy in hepatic insulin resistance: Therapeutic potential and concerns. Front Pharmacol 2019;10:1193. 
23. Lemasters JJ, Zhong Z. Mitophagy in hepatocytes: Types, initiators and role in adaptive ethanol  metabolism. Liver Res 2018;2:125–132. 
24. Wang H, Ni H-M, Chao X, Ma X, Rodriguez YA, Chavan H, et al. Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates  acetaminophen-induced liver injury in mice. Redox Biol 2019;22:101148. 
25. Moreira OC, Estébanez B, Martínez-Florez S, de Paz JA, Cuevas MJ, González-Gallego J. Mitochondrial function and mitophagy in the elderly: Effects of exercise. Oxid Med Cell Longev 2017;2017:2012798. 
26. Eid N, Ito Y, Otsuki Y. Triggering of parkin mitochondrial translocation in mitophagy: Implications for  liver diseases. Front Pharmacol 2016;7:100. 
27. Glick D, Zhang W, Beaton M, Marsboom G, Gruber M, Simon MC, et al. BNip3 regulates mitochondrial function and lipid metabolism in the liver. Mol Cell Biol 2012;32:2570–2584. 
28. Oyewole AO, Birch-Machin MA. Mitochondria-targeted anti-oxidants. FASEB J 2015;29:4766–4671. 
29. Cohen SD, Pumford NR, Khairallah EA, Boekelheide K, Pohl LR, Amouzadeh HR, et al. Selective protein covalent binding and target organ toxicity. Toxicol Appl Pharmacol 1997;143:1–12. 
30. Du K, Farhood A, Jaeschke H. Mitochondria-targeted anti-oxidant Mito-Tempo protects against acetaminophen hepatotoxicity. Arch Toxicol 2017;91:761–773. 
31. Ahmed LA, Shehata NI, Abdelkader NF, Khattab MM. Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice. PLoS One 2014;9:e108889. 
32. Dey S, DeMazumder D, Sidor A, Foster DB, O’Rourke B. Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in  heart failure. Circ Res 2018;123:356-371. 
33. Gunadi JW, Tarawan VM, Daniel Ray HR, Wahyudianingsih R, Lucretia T, Tanuwijaya F, et al. Different training intensities induced autophagy and histopathology appearances potentially associated with lipid metabolism in wistar rat liver. Heliyon 2020;6:e03874. 
34. Tarawan VM, Gunadi JW, Setiawan, Lesmana R, Goenawan H, Meilina DE, et al. Alteration of autophagy gene expression by different intensity of exercise in  gastrocnemius and soleus muscles of wistar rats. J Sports Sci Med 2019;18:146-154. 
35. Lesmana R, Budi Prasetyo W, Ray HRD, Tarawan V, Goenawan H, Setiawan I, et al. Exercise serum alters genes related mitochondria in cardiomyocyte culture cell. J Pendidik Jasm dan Olahraga 2020;5:102-110. 
36. Maurya SK, Herrera JL, Sahoo SK, Reis FCG, Vega RB, Kelly DP, et al. Sarcolipin signaling promotes mitochondrial biogenesis and oxidative metabolism in  skeletal muscle. Cell Rep 2018;24:2919-2931. 
37. Montagna C, Di Giacomo G, Rizza S, Cardaci S, Ferraro E, Grumati P, et al. S-nitrosoglutathione reductase deficiency-induced S-nitrosylation results in neuromuscular dysfunction. Anti-oxid Redox Signal 2014;21:570-587. 
38. Hong JY, Kim H, Lee J, Jeon W-J, Baek SH, Ha I-H. Neurotherapeutic Effect of Inula britannica var. chinensis against H(2)O(2)-induced oxidative stress and mitochondrial dysfunction in cortical neurons. Anti-oxidants 2021;10:375. 
39. Abdullaev S, Gubina N, Bulanova T, Gaziev A. Assessment of nuclear and mitochondrial DNA, expression of mitochondria-related genes in different brain regions in rats after whole-body X-ray irradiation. Int J Mol Sci 2020;21:1196. 
40. Yin P, Wan C, He S, Xu X, Liu M, Song S, et al. Transport stress causes damage in rats’ liver and triggers liver autophagy. Biotechnol An Indian J 2013;8:1561-1566. 
41. Kowalik MA, Perra A, Ledda-Columbano GM, Ippolito G, Piacentini M, Columbano A, et al. Induction of autophagy promotes the growth of early preneoplastic rat liver nodules. Oncotarget 2016;7:5788-5799. 
42. Wang K, Wang F, Bao J-P, Xie Z-Y, Chen L, Zhou B-Y, et al. Tumor necrosis factor α modulates sodium-activated potassium channel SLICK in rat  dorsal horn neurons via p38 MAPK activation pathway. J Pain Res 2017;10:1265-1271. 
43. Eleazu CO, Iroaganachi M, Okafor PN, Ijeh II, Eleazu KC. Ameliorative potentials of ginger (Zingiber officinale Roscoe) on relative organ weights in streptozotocin induced diabetic rats. Int J Biomed Sci 2013;9:82-90. 
44. Eleazu CO, Iroaganachi M, Eleazu KC. Ameliorative potentials of cocoyam (Colocasia esculenta L.) and unripe plantain  (Musa paradisiaca L.) on the relative tissue weights of streptozotocin-induced diabetic rats. J Diabetes Res 2013;2013:160964. 
45. Adeghate E, Ponery AS. GABA in the endocrine pancreas: cellular localization and function in normal and  diabetic rats. Tissue Cell 2002;34:1–6. 
46. Ho J, Tseng C-Y, Ma W-H, Ong W-K, Chen Y-F, Chen M-H, et al. Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and β-Cell differentiation in streptozocin-induced diabetic mice. Cell Transplant 2011;21:997-1009. 
47. Vivek KS. Streptozotocin: An experimental tool in diabetes and alzheimer’s disease: A review. Int J Pharma Res Dev 2010;2:1-7. 
48. Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017;27:1147–1151. 
49. Trnka J, Blaikie F, Logan A, Smith R, Murphy M. Anti-oxidant properties of MitoTEMPOL and its hydroxylamine. Free Radic Res 2009;43:4–12. 
50. Wu J, Zheng L, Mo J, Yao X, Fan C, Bao Y. Protective effects of MitoTEMPO on nonalcoholic fatty liver disease via regulating myeloid-derived suppressor cells and inflammation in mice. Biomed Res Int 2020;2020:9329427. 
51. Ma Y, Huang Z, Zhou Z, He X, Wang Y, Meng C, et al. A novel anti-oxidant Mito-Tempol inhibits ox-LDL-induced foam cell formation through restoration of autophagy flux. Free Radic Biol Med 2018;129:463–472. 
52. Guven A, Yavuz O, Cam M, Ercan F, Bukan N, Comunoglu C, et al. Effects of melatonin on streptozotocin-induced diabetic liver injury in rats. Acta Histochem 2006;108:85–93. 
53. Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Anti-oxid Redox Signal 2010;12:537–77. 
54. Durcan TM, Fon EA. The three ’P’s of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes Dev 2015;29:989-999. 
55. Twig G, Shirihai OS. The interplay between mitochondrial dynamics and mitophagy. Anti-oxid Redox Signal  2011;14:1939-1951. 
56. Van der Bliek AM, Shen Q, Kawajiri S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb Perspect Biol 2013;5:a011072. 
57. Williams M, Caino MC. Mitochondrial dynamics in type 2 diabetes and cancer. Front Endocrinol 2018;9:211. 
58. Bereiter-Hahn J, Vöth M. Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and  fission of mitochondria. Microsc Res Tech 1994;27:198-219. 
59. Amiri M, Hollenbeck PJ. Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev Neurobiol 2008;68:1348-1361. 
Iranian Journal of Basic Medical Sciences
Volume 25, Issue 11
November 2022
Pages 1382-1388

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