A.V. ZATVORNITSKAYA^1, 2, E.L. KAZACHKOV¹, E.A. KAZACHKOVA¹, N.V. KAZANTSEVA³

¹South Ural State Medical University, Chelyabinsk

²Ural Research Institute for Maternity and Child Care, Yekaterinburg

³Sverdlovsk Region Oncology Dispensary, Yekaterinburg

Contact details:

Zatvornitskaya A.V. — PhD (Medicine), Associate Professor of the Department of Pathological Anatomy and Forensic Medicine named after Prof. V.L. Kovalenko, Head of the 1^st Obstetrics Department of Pregnancy Pathology

Address: 64 Vorovskogo St., 454141 Chelyabinsk, Russian Federation, tel.: +7-919-400-75-35, e-mail: monostyle@list.ru

Malignization is characterized by changes in mitochondrial metabolism, highlighting the role of mitochondrial transcription factor A (TFAM) as a key regulator of mitochondrial biogenesis. Changes in iNOS activity and elevated nitric oxide levels can directly damage mitochondrial DNA and proteins, including TFAM, leading to impaired mitochondrial biogenesis and increased nitrosative stress. The relationship between mitochondrial dysfunction and nitrosative stress was been extensively studied in preeclampsia, neurodegenerative diseases, hypertension, and heart failure. However, the correlations between these processes in precancerous and cancerous diseases of the endometrium remain underexplored. The studies devoted to mitochondrial dysfunction and nitrosative stress in endometrial hyperplasia and cancer are isolated and contradictory.

The purpose — to evaluate the interacting factors of mitochondrial dysfunction and nitrosative stress in endometrial tissue in precancerous lesions and endometrial carcinoma.

Material and methods. A retrospective cohort single-center study using histological, immunohistochemical (IHC), and statistical research methods.

Results. The IHC study of endometrial samples from precancerous conditions and endometrial carcinoma revealed cascading changes of TFAM and iNOS expression levels, which convincingly indicates the presence of nitrosative stress and mitochondrial dysfunction.

Conclusion. An integrative approach to assessing mitochondrial status and nitrosative stress opens new perspectives for early diagnosis and therapy of endometrial precancer and cancer.

Key words: endometrial hyperplasia, endometrioid carcinoma, mitochondrial dysfunction, nitrosative stress

REFERENCES

1. Podzolkova N.M., Karpov A.A., Lebedev S.S., Kuznetsov R.E., Denisova Yu.V., Alimov V.A. et al. Atypical endometrial hyperplasia and early stages of endometrial cancer: controversial aspects of terminology, classification, diagnosis, and treatment. Ginekologiya, 2025, no. 27 (4), pp. 272–280 (in Russ.). DOI: 10.26442/20795696.2025.4.203511
2. Potemina T.E., Guzikov E.V. Mitochondrial changes in carcinogenesis as a target of antitumor therapy (review). Informatsionnyy byulleten′ Meditsinskogo instituta «Reaviz», 2020, no. 4, pp. 65–73 (in Russ.).
3. Kozhukhar N., Alexeyev M.F. 35 Years of TFAM research: old protein, new puzzles. Biology (Basel), 2023, vol. 12 (6), p. 823. DOI: 10.3390/biology12060823
4. Litvinova L., Atochin D.N., Fattakhov N., Vasilenko M., Zatolokin P., Kirienkova E. Nitric oxide and mitochondria in metabolic syndrome. Front. Physiol, 2015, vol. 17 (6), p. 20. DOI: 10.3389/fphys.2015.00020
5. Jiang M., Li J., Ding N., Jia G., Wu S., Liu N. et al. SIRT6-mediated regulation of TFAM: a central mechanism connecting nuclear and mitochondrial transcriptional processes and mitophagy. Int. J. Biol. Sci, 2026, vol. 22 (1), pp. 178–200. DOI: 10.7150/ijbs.120007
6. Salis Torres A., Lee J.E., Caporali A., Semple R.K., Horrocks M.H., MacRae V.E. Mitochondrial dysfunction as a potential mechanism mediating cardiac comorbidities in Parkinson’s disease. Int. J. Mol. Sci, 2024, vol. 25 (20), pp. 10973. DOI: 10.3390/ijms252010973
7. Perfilova V.N. The role of placental mitochondria in the etiology and pathogenesis of complicated pregnancy. Akusherstvo i ginekologiya, 2019, no. 4, pp. 5–11 (in Russ.). DOI: 10.18565/aig.2019.4.5-11
8. Nunes C., Laranjinha J. Nitric oxide and dopamine metabolism converge via mitochondrial dysfunction in the mechanisms of neurodegeneration in Parkinson’s disease. Arch. Biochem. Biophys, 2021, vol. 704, p. 108877. DOI: 10.1016/j.abb.2021.108877
9. Allerton T.D., Stampley J.E., Li Z., Yu X., Quiariate H., Doiron J.E. et al. Nitric oxide donors rescue metabolic and mitochondrial dysfunction in obese Alzheimer’s model. Sci. Rep, 2024, vol. 14 (1), p. 26118. DOI: 10.1038/s41598-024-75870-8
10. Dikalova A., Fehrenbach D., Mayorov V., Panov A., Ao M., Lantier L. et al. Mitochondrial CypD acetylation promotes endothelial dysfunction and hypertension. Circ. Res., 2024, vol. 134 (11), pp. 1451–1464. DOI: 10.1161/CIRCRESAHA.123.323596
11. Guo Y., Wen J., He A., Qu C., Peng Y., Luo S. et al. iNOS contributes to heart failure with preserved ejection fraction through mitochondrial dysfunction and Akt S-nitrosylation. J. Adv. Res, 2023, vol. 43, pp. 175–186. DOI: 10.1016/j.jare.2022.03.003
12. Wang T., Zhang J., Hu M., Zhang Y., Cui P., Li X. et al. Differential expression patterns of glycolytic enzymes and mitochondria-dependent apoptosis in PCOS patients with endometrial hyperplasia, an early hallmark of endometrial cancer, in vivo and the impact of metformin in vitro. Int. J. Biol. Sci, 2019, vol. 15 (3), pp. 714–725. DOI: 10.7150/ijbs.31425
13. Bogdanov L.A., Kutikhin A.G Optimization of staining of elements of the circulatory system and hepatosplenic system with hematoxylin and eosin. Fundamental′naya i klinicheskaya meditsina, 2019, vol. 4 (4), pp. 70–77 (in Russ.). DOI: 10.23946/2500 0764-2019-4-4-70-7
14. Bankhead P., Loughrey M.B., Fernández J.A., Dombrowski Y., McArt D.G., Dunne P.D. et al. QuPath: Open source software for digital pathology image analysis. Sci. Rep., 2017, vol. 7 (1), p. 16878. DOI: 10.1038/s41598-017-17204-5
15. Schroeder A.B., Dobson E.T.A., Rueden C.T., Tomancak P., Jug F., Eliceiri K.W. The ImageJ ecosystem: open-source software for image visualization, processing, and analysis. Protein Sci, 2021, vol. 30 (1), pp. 234–249. DOI: 10.1002/pro.3993
16. Gerasimov A.N., Morozova N.I. Parametric and nonparametric methods in medical statistics. Epidemiologiya i vaktsinoprofilaktika, 2015, vol. 14 (5), pp. 6–12 (in Russ.). DOI: 10.31631/2073-3046-2015-14-5-6-12
17. Yang S., He X., Zhao J., Wang D., Guo S., Gao T. et al. Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer. Cancer Commun (Lond), 2021, vol. 41 (8), pp. 695–714. DOI: 10.1002/cac2.12184
18. Shen Q., Fang J., Guo H., Su X., Zhu B., Yao X. et al. Astragaloside IV attenuates podocyte apoptosis through ameliorating mitochondrial dysfunction by up-regulated Nrf2-ARE/TFAM signaling in diabetic kidney disease. Free Radic. Biol. Med, 2023, vol. 203, pp. 45–57. DOI: 10.1016/j.freeradbiomed.2023.03.022
19. Kunkel G.H., Chaturvedi P., Tyagi S.C. Mitochondrial pathways to cardiac recovery: TFAM. Heart Fail Rev, 2016, vol. 21 (5), pp. 499–517. DOI: 10.1007/s10741-016-9561-8
20. Marcos-Ríos D., Rochano-Ortiz A., Méndez-Barbero N., Oller J. Defective mitochondrial respiration in hereditary thoracic aneurysms. Cells, 2025, vol. 14 (11), p. 768. DOI: 10.3390/cells14110768
21. Anselme M., He H., Lai C., Luo W., Zhong S. Targeting mitochondrial transporters and metabolic reprogramming for disease treatment. J. Transl. Med, 2025, vol. 23 (1), p. 1111. DOI: 10.1186/s12967-025-06976-4
22. Li Y., Yang Q., Chen H., Yang X., Han J., Yao X. et al. TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway. Oncogene, 2022, vol. 41 (30), pp. 3735–3746. DOI: 10.1038/s41388-022-02365-z
23. Kuracinova T., Bollova M., Kocan D., Mikus Kuracinova K., Janegova A., Janega P. Nitric oxide synthase expression in endometrium during physiological cycle. Physiol. Res, 2025, vol. 74 (suppl 2), pp. S285–S292. DOI: 10.33549/physiolres.935735
24. Cinelli M.A., Do H.T., Miley G.P., Silverman R.B. Inducible nitric oxide synthase: Regulation, structure, and inhibition. Med. Res. Rev, 2020, vol. 40 (1), pp. 158–189. DOI: 10.1002/med.21599
25. Cinel L., Polat A., Aydin O., Düşmez D., Eğilmez R. Bcl-2, iNOS, p53 and PCNA expression in normal, disordered proliferative, hyperplastic and malignant endometrium. Pathol. Int, 2002, vol. 52 (5–6), pp. 384–389. DOI: 10.1046/j.1440-1827.2002.01358.x