Deciphering the Role of Mitochondrial Metabolic Reprogramming in the Progression of Clear Cell Renal Cell Carcinoma

• Suresh Chandra Yadav

  Kalinga University, Naya Raipur, Chhattisgarh, India

• Dilip Dwivedy

  Kalinga University, Naya Raipur, Chhattisgarh, India

The most prevalent and aggressive type of kidney cancer, which is known to be difficult to treat with standard therapies and has a poor prognosis, is clear cell renal cell carcinoma (ccRCC). It has been suggested that mitochondrial metabolic reprogramming is now a fundamental component of the development of ccRCC that affects energy generation, cell survival, and tumor aggressiveness. The aim of the study is to examine the importance of mitochondrial dysfunction in cRCC through imaging the metabolic changes that occur in the tumor microenvironment. A multi-omics method is used, which combines transcriptomic, metabolomic, and proteomic studies to reveal the metabolic changes that occur in the cells of ccRCC. Found that there were marked changes in some of the important metabolic pathways, such as increased glycolysis and fatty acid oxidation, as well as a significant decrease in the efficiency of oxidative phosphorylation. These were associated with metabolic alterations that correlated with a higher tumor cell survival and expansion in hypoxic conditions, which is typical of ccRCC. Moreover, several important regulators of metabolism, including HIF-1α, AMPK, and PGC-1α, were overexpressed in ccRCC cells and linked to the metabolic changes. Although HIF-1α, AMPK, and PGC-1α emerge as possible therapeutic targets, this paper does not involve any inhibition studies that would demonstrate the therapeutic value of these targets. The evidence presented here is purely correlational, involving only cell line and xenograft models. The given study contributes to the understanding of the metabolic weakness of the ccRCC and refers to the possibility of developing new treatment modalities that could influence the metabolism of mitochondria. Future studies ought to ultimately be on clinical validation of these findings and investigations on the development of mitochondrial-targeted therapies as monotherapies or as adjuncts to existing therapies in order to enhance patient outcomes in ccRCC.

[1] Zhang Y, Zhang S, Sun H, Xu L. The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma. Cell Death Discovery 2025; 11(1): 186.

[2] Hu J, Wang SG, Hou Y, Chen Z, Liu L, Li R, et al. Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression. Nature Genetics 2024; 56(3): 442-457.

[3] Wu G, Li T, Chen Y, Ye S, Zhou S, Tian X, et al. Deciphering glutamine metabolism patterns for malignancy and tumor microenvironment in clear cell renal cell carcinoma. Clinical and Experimental Medicine 2024; 24(1): 152.

[4] Balamanikandan A, Saravanakumar M, Gunasekaran S, Anjum V, Gurusamy P, Ashokkumar N. Deep learning in the detection of chronic kidney disease. In: 2023 4th International Conference on Intelligent Technologies (CONIT) 2024; 1-6.

[5] Zhan M, Zhao B, Chen H, Wu J, Shi R, Gao F, et al. Metabolic reprogramming in clear cell renal cell carcinoma: core pathways and targeted therapeutic strategies. Frontiers in Genetics 2025; 16: 1752384.

[6] Abduljabbar MK, Merza M, Aziz A, Menon SV, Kaur M, Aminov Z, et al. Lipid metabolism reprogramming in renal cell carcinomas. Medical Oncology 2024; 41(10): 243.

[7] Heravi G, Yazdanpanah O, Podgorski I, Matherly LH, Liu W. Lipid metabolism reprogramming in renal cell carcinoma. Cancer and Metastasis Reviews 2022; 41(1): 17-31.

[8] Lu D, Li Y, Niu X, Sun J, Zhan W, Shi Y, et al. STAT2/SLC27A3/PINK1-mediated mitophagy remodeling lipid metabolism contributes to pazopanib resistance in clear cell renal cell carcinoma. Research 2024; 7: 0539.

[9] Bischoff ME, Shamsaei B, Yang J, Secic D, Vemuri B, Reisz JA, et al. Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma. Cancer Discovery 2025; 15(2): 401-426.

[10] Boymuradov S, Ugli ERS, Abbas HM, Ramanathan CR, Biswas D. Microbial fuel cells in sustainable aquatic ecosystem management for energy and pollution control. International Journal of Aquatic Research and Environmental Studies 2025; 5(2): 347-359.

[11] Hua ZL. Elucidating the Role of Cytochrome p450 Enzymes in Drug Metabolism and Interactions. Clinical Journal for Medicine, Health and Pharmacy 2024; 2(3): 1-10.

[12] Fan X, Yang M, Lang Y, Lu S, Kong Z, Gao Y, et al. Mitochondrial metabolic reprogramming in diabetic kidney disease. Cell Death & Disease 2024; 15(6): 442.

[13] Chugh M, Srishti P, Sidhu J, Vashisht N, Sudhakar Reddy M, Patel DJ. Optimizing machine learning-based algorithms for urea detection in biomedical applications. Journal of Wireless Mobile Networks, Ubiquitous Computing, and Dependable Applications 2025; 16(4): 285-305.

[14] Saxena S, Dagar N, Shelke V, Lech M, Khare P, Gaikwad AB. Metabolic reprogramming: Unveiling the therapeutic potential of targeted therapies against kidney disease. Drug Discovery Today 2023; 28(11): 103765.

[15] Fei C, Zhen X, Shiqiang Z, Jun P. Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma. Cell Death Discovery 2024; 10(1): 113.

[16] Zairov N, Tulakov R, Khasanov U, Rakhmanovich IU, Temirkulova N, Uzakbaeva B, Geldiev B. Impact of animal-caused air and water pollution on the incidence of chronic kidney disease in urban populations. Journal of Animal Environment 2025; 17(2): 257-267.

[17] Sun S, Su D, Dong T, Wang B, Ji X, Chu L, et al. Mitochondrial ribosomal protein L12 mediates metabolic reorganization in clear cell renal cell carcinoma by regulating mitochondrial biosynthesis. Cell Communication and Signaling 2025; 23(1): 435.

[18] Mao Y, Xia Z, Xia W, Jiang P. Metabolic reprogramming, sensing, and cancer therapy. Cell Reports 2024; 43(12).

[19] Wang J, Chang H, Su M, Qiao Y, Sun H, Zhao Y, et al. Identification of HGD and GSTZ1 as biomarkers involved metabolic reprogramming in kidney renal clear cell carcinoma. International Journal of Molecular Sciences 2022; 23(9): 4583.

[20] Yu W, Chen Y, Putluri N, Osman A, Coarfa C, Putluri V, et al. Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state. British Journal of Cancer 2023; 128(11): 2013-2024.

• PDF

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.