Mitochondrial genome alterations in cancer: From mutations and epigenetics to targeted therapiesack.

Mitochondria play a central role in cellular energetics, metabolism, and apoptosis, and their dysfunction is increasingly recognized as a hallmark of cancer. The mitochondrial genome encodes essential subunits of oxidative phosphorylation (OXPHOS) complexes, tRNAs, and rRNAs, which are critical for mitochondrial functions.

However, mitochondrial DNA (mtDNA) lacks protective histones and efficient repair mechanisms, rendering it highly susceptible to mutations and epigenetic changes. This review examines the role of mitochondrial-encoded genes (MEGs) in cancer progression, emphasizing the molecular mechanisms through which alterations in these genes contribute to tumorigenesis. We discuss how microsatellite instability, somatic mutations, and epigenetic modifications, such as methylation and non-coding RNA interactions, disrupt mitochondrial function, leading to defective OXPHOS, metabolic reprogramming (including the Warburg effect), elevated reactive oxygen species (ROS) production, and evasion of apoptosis.

Furthermore, we highlight the tissue-specific and stage-dependent alterations in MEGs across various cancers, including breast, colorectal, lung, and ovarian malignancies, and explore their potential as diagnostic, prognostic, and therapeutic biomarkers. Finally, we evaluate emerging therapeutic strategies targeting MEGs, including mitochondrial gene editing, allotopic expression, and nanocarrier-based delivery systems, offering insights into future directions in precision oncology. We also discuss how MEG alterations contribute to the Warburg effect, chemoresistance, and tumor metastasis, which are critical barriers to effective cancer treatment. This synthesis highlights the pivotal role of mitochondrial genetics in cancer biology and positions MEGs as promising targets for innovative anticancer therapies.