Mitochondrial Dysfunction in Renal Cell Carcinoma: A Comprehensive Review of Pathogenic Mechanisms and Emerging...

In renal cell carcinoma (RCC), alterations in cellular metabolism are a defining feature, among which impaired mitochondrial function stands out as a key factor influencing both tumor aggressiveness and patient responses to therapy. The aim of this review is to systematically synthesize current knowledge on the role of mitochondrial dysfunction in RCC pathogenesis and to explore emerging therapeutic strategies targeting mitochondrial vulnerabilities. This comprehensive analysis examines the integrated dysregulation of core mitochondrial processes-bioenergetic metabolism, organelle dynamics, programmed cell death pathways, redox homeostasis, and selective autophagy-in driving RCC pathogenesis. Our synthesis reveals how genetic drivers, molecular regulators, and microenvironmental cues converge to remodel mitochondrial function, creating both adaptive advantages and therapeutic vulnerabilities. A paradoxical duality emerges in mitochondrial biology: processes such as fission, mitophagy, and reactive oxygen species (ROS) generation can simultaneously support tumor adaptation while rendering cells susceptible to targeted interventions. We evaluate emerging therapeutic approaches directed at mitochondrial vulnerabilities, including metabolic inhibitors, nanoscale delivery systems, and phytochemical agents, while addressing current limitations in specificity and resistance mechanisms. Based on current preclinical evidence, this integrated perspective establishes mitochondrial dysfunction as a central determinant of RCC malignancy and suggests potential combinatorial strategies for precision oncology approaches that warrant further investigation.