Functional state of cardiomyocyte mitochondria in malignant process in presence of comorbid pathology in experiment

Purpose of the study. An analysis of indices of free radical oxidation and respiration of mitochondria of heart cells in a malignant process in presence of diabetes mellitus and chronic neurogenic pain in experimental animals.
Materials and methods. The study included outbred female rats (n=32) and С57ВL/6 female mice (n=84). Experimental groups of rats were: intact group 1 (n=8), control group 1 (n=8) with diabetes mellitus (DM), comparison group 1 (n=8) with standard subcutaneous transplantation of Guerin’s carcinoma, main group 1 (n=8) with Guerin’s carcinoma transplanted after 1 week of persistent hyperglycemia. Experimental groups of mice were: intact group 2 (n=21), control group 2 (n=21) with a model of chronic neurogenic pain (CNP), comparison group 2 (n=21) with standard subcutaneous transplantation of melanoma (B16/F10), main group 2 (n=21) (CNP+B16/F10) with melanoma transplanted 3 weeks after the CNP model creation. Heart mitochondria were isolated by differential centrifugation. Levels of cytochrome C (ng/mg of protein), 8-hydroxy-2'-deoxyguanosine (8-OHdG) (ng/mg of protein), and malondialdehyde (MDA) (μmol/g of protein) were measured in mitochondrial samples by ELISA. Statistical analysis was performed using the Statistica 10.0 program.
Results. DM in rats upregulated 8-OHdG by 6.3 times and MDA by 1.9 times (р=0.0000) and downregulated cytochrome C by 1.5 times (р=0.0053) in heart cell mitochondria, compared to intact values. DM+Guerin’s carcinoma in rats increased 8-OHdG by 14.0 times and MDA by 1.7 times (р=0.0000) and decreased cytochrome C by 1.5 times (р=0.0000), compared to intact values. CNP in mice did not affect the studied parameters in mitochondria of the heart. CNP+B16/F10 in mice increased 8-OHdG by 7.1 times and MDA by 1.6 times (р=0.0000) and decreased cytochrome C by 1.6 times (р=0.0008).
Conclusions. Comorbidity (diabetes mellitus, chronic neurogenic pain) together with malignant pathology aggravates mitochondrial dysfunction of heart cells with destabilization of the respiratory chain mediated by free radical oxidation processes.

1. Coughlin SS, Ayyala D, Majeed B, Cortes L, Kapuku G. Cardiovascular Disease among Breast Cancer Survivors. Cardiovasc Disord Med. 2020;2(1). https://doi.org/10.31487/j.cdm.2020.01.01

2. Kaprin AD, Matskeplishvili ST, Potievskaya VI, Popovkina OE, Bolotina LV, Shklyaeva AV, Poluektova MV. Cardiovascular diseases in cancer patients. Oncology. Journal named after P.A.Herzen. 2019;8(2):139–147. (In Russian). https://doi.org/10.17116/onkolog20198021139

3. Cignarelli A, Genchi VA, Caruso I, Natalicchio A, Perrini S, Laviola L, et al. Diabetes and cancer: Pathophysiological fundamentals of a “dangerous affair.” Diabetes Res Clin Pract. 2018 Sep;143:378–388. https://doi.org/10.1016/j.diabres.2018.04.002

4. Leppert W, Zajaczkowska R, Wordliczek J, Dobrogowski J, Woron J, Krzakowski M. Pathophysiology and clinical characteristics of pain in most common locations in cancer patients. J Physiol Pharmacol. 2016 Dec;67(6):787–799.

5. Louwagie EJ, Larsen TD, Wachal AL, Gandy TCT, Baack ML. Mitochondrial Transfer Improves Cardiomyocyte Bioenergetics and Viability in Male Rats Exposed to Pregestational Diabetes. Int J Mol Sci. 2021 Feb 27;22(5):2382. https://doi.org/10.3390/ijms22052382

6. Frantsiyants EM, Neskubina IV, Surikova EI, Shikhlyarova AI, Kaplieva IV, Nemashkalova LA, et al. The state of apoptosis factor system in mitochondria of skin and tumor cells in standard and stimulated growth of B16/F10 melanoma in female C57BL/6 mice. Research and Practical Medicine Journal. 2021;8(1):8–19. (In Russian). https://doi.org/10.17709/2409-2231-2021-8-1-1

7. Kit OI, Frantsiyants EM, Neskubina IV, Surikova EI, Kaplieva IV, Bandovkina VA. Influence of B16/F10 melanoma growth variant on calcium levels in mitochondria in various organs of female mice. Research and Practical Medicine Journal. 2021;8(1):20–29. (In Russian). https://doi.org/10.17709/2409-2231-2021-8-1-2

8. Murphy E, Ardehali H, Balaban RS, DiLisa F, Dorn GW, Kitsis RN, et al. Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association. Circ Res. 2016 Jun 10;118(12):1960–1991. https://doi.org/10.1161/RES.0000000000000104

9. Sabri A, Hughie HH, Lucchesi PA. Regulation of hypertrophic and apoptotic signaling pathways by reactive oxygen species in cardiac myocytes. Antioxid Redox Signal. 2003 Dec;5(6):731– 740. https://doi.org/10.1089/152308603770380034

10. Sun X, Alford J, Qiu H. Structural and Functional Remodeling of Mitochondria in Cardiac Diseases. Int J Mol Sci. 2021 Apr 17;22(8):4167. https://doi.org/10.3390/ijms22084167

11. Murphy E, Ardehali H, Balaban RS, DiLisa F, Dorn GW, Kitsis RN, et al. Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association. Circ Res. 2016 Jun 10;118(12):1960–1991. https://doi.org/10.1161/RES.0000000000000104

12. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009 Jan 1;417(1):1–13. https://doi.org/10.1042/BJ20081386

13. Mdaki KS, Larsen TD, Wachal AL, Schimelpfenig MD, Weaver LJ, Dooyema SDR, et al. Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction. Am J Physiol Heart Circ Physiol. 2016 Mar 15;310(6):H681–H692. https://doi.org/10.1152/ajpheart.00795.2015

14. Münzel T, Gori T, Keaney JF, Maack C, Daiber A. Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications. Eur Heart J. 2015 Oct 7;36(38):2555–2564. https://doi.org/10.1093/eurheartj/ehv305

15. Oguntibeju OO. Type 2 diabetes mellitus, oxidative stress and inflammation: examining the links. Int J Physiol Pathophysiol Pharmacol. 2019;11(3):45–63.

16. Patti M-E, Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev. 2010 Jun;31(3):364–395. https://doi.org/10.1210/er.2009-0027

17. Treede R-D, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008 Apr 29;70(18):1630–1635. https://doi.org/10.1212/01.wnl.0000282763.29778.59

18. Kuhner R, Flor H. Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci. 2016 Dec 15;18(1):20–30. https://doi.org/10.1038/nrn.2016.162

19. Kit OI, Kotieva IM, Frantsiyants EM, Kaplieva IV, Trepitaki LK, Bandovkina VA, et al. Influence of chronic neuropathic pain on the course of malignant В16/F10 melanoma in male mice. News of Higher Educational Institutions. The North Caucasus Region. Series: Natural Sciences. 2019;(1(201)):106–111. (In Russian).

20. Egorova MV, Afanasyev SA. Isolation of mitochondria from cells and tissues of animals and human: Modern methodical approaches. Siberian Medical Journal. 2011;26(1-1):22–28. (In Russian).

21. Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2’ -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2009 Apr;27(2):120–139. https://doi.org/10.1080/10590500902885684

22. Frantsiyants EM, Neskubina IV, Shikhlyarova AI, Cheryarina ND, Kaplieva IV, Bandovkina VA, et al. The effect of diabetes mellitus under tumor growth on respiratory function and free radical processes in heart cell mitochondria in rats. Cardiometry. 2021;18:50–55. https://doi.org/10.18137/cardiometry.2021.18.5055

23. Kiyuna LA, Albuquerque RPE, Chen C-H, Mochly-Rosen D, Ferreira JCB. Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities. Free Radic Biol Med. 2018 Dec;129:155–168. https://doi.org/10.1016/j.freeradbiomed.2018.09.019

24. Voulgaridou G-P, Anestopoulos I, Franco R, Panayiotidis MI, Pappa A. DNA damage induced by endogenous aldehydes: current state of knowledge. Mutat Res. 2011 Jun 3;711(1– 2):13–27. https://doi.org/10.1016/j.mrfmmm.2011.03.006

25. Santucci R, Sinibaldi F, Cozza P, Polticelli F, Fiorucci L. Cytochrome c: An extreme multifunctional protein with a key role in cell fate. Int J Biol Macromol. 2019 Sep 1;136:1237–1246. https://doi.org/10.1016/j.ijbiomac.2019.06.180

26. Kim-Campbell N., Gomez H., Bayir H. Chapter 20—Cell death pathways: Apoptosis and regulated necrosis. In: Ronco C., Bellomo R., Kellum J.A., Ricci Z., editors. Critical Care Nephrology. 3rd ed. Elsevier; Philadelphia, PA, USA. 2019:113– 121. https://doi.org/10.1016/B978-0-323-44942-7.00020-0

27. Frantsiyants EM, Neskubina IV, Shikhlyarova AI, Yengibaryan MA, Vashenko LN, Surikova EI, et al. Content of apoptosis factors and self-organization processes in the mitochondria of heart cells in female mice C57BL/6 under growth of melanoma B16/F10 linked with comorbid pathology. Cardiometry. 2021;18:121–130. https://doi.org/10.18137/cardiometry.2021.18.121130