Mitochondria are essential organelles that coordinate cellular energetics, intermediary metabolism, and programmed cell death. Dysfunctional mitochondria are increasingly recognized as a hallmark of cancer. The mitochondrial genome encodes critical components required for electron transport and ATP production; alterations in these mitochondrial-encoded genes (MEGs) can therefore have profound effects on cellular physiology and tumor biology.
The mitochondrial genome is inherently more susceptible to damage than nuclear DNA because it lacks protective histones and possesses less efficient DNA repair pathways. This vulnerability contributes to the accumulation of diverse alterations, including somatic mutations, microsatellite instability, and epigenetic modifications. Epigenetic mechanisms described include DNA methylation and regulatory interactions with non-coding RNAs, which together with sequence changes can perturb the expression and function of MEGs.
Alterations in MEGs impair the integrity and function of mitochondrial-encoded subunits of the electron transport chain. Disruption of these subunits leads to defective OXPHOS and shifts in cellular metabolism. Mechanistic consequences noted include metabolic reprogramming toward glycolysis (the Warburg effect), increased generation of reactive oxygen species (ROS), and impaired apoptotic signaling. These molecular perturbations create a cellular environment that can favor malignant transformation, proliferation, and survival under stress.
Loss of mitochondrial respiratory competence through MEG alterations compromises ATP generation via oxidative phosphorylation and promotes compensatory metabolic pathways. The review links these changes to the classical metabolic shift observed in many tumors, where glycolytic metabolism is favored despite oxygen availability. Elevated ROS from dysfunctional mitochondria can further damage cellular macromolecules and modulate signaling pathways that support tumor progression. Concurrently, disruptions in mitochondrial regulation of apoptosis contribute to cell survival, resistance to cytotoxic insults, and therapeutic escape.
MEG alterations are not uniform across cancers; the review highlights that patterns of mtDNA change are often tissue-specific and can vary with tumor stage. Examples discussed in the abstract include alterations observed in breast, colorectal, lung, and ovarian malignancies. These differences underscore the complexity of mitochondrial involvement in cancer and suggest that the impact of any single mtDNA change must be interpreted in a context-dependent manner.
Because MEG alterations can reflect functional shifts in tumor metabolism and survival pathways, the authors emphasize their potential as biomarkers. Mitochondrial mutations and mitoepigenetic signatures may serve diagnostic or prognostic roles, and could inform patient stratification in precision oncology. The abstract positions MEG-related markers as promising complements to existing nuclear genomic and proteomic biomarkers, though specific marker panels or clinical validation data are not provided in the abstract.
The review summarizes emerging therapeutic approaches aimed directly at mitochondrial genomes and their gene products. Strategies described include mitochondrial gene editing to correct or disrupt pathogenic mtDNA variants, allotopic expression where mitochondrial proteins are expressed from nuclear constructs and imported into mitochondria, and nanocarrier-based delivery systems to transport nucleic acids or therapeutics to mitochondria. These approaches are presented as innovative avenues for translating knowledge of MEG biology into targeted cancer treatments.
While the abstract synthesizes the role of MEG alterations in cancer biology and outlines therapeutic concepts, it does not present primary clinical trial outcomes or detailed quantitative results. The complexity of delivering therapies to mitochondria, potential off-target effects, and the tissue- and stage-dependent nature of MEG changes are implied challenges. The authors indicate that continued research into mitochondrial genetics, mitoepigenetics, and delivery technologies is needed to realize clinical translation.
The reviewed literature positions mitochondrial genetics as a pivotal component of cancer biology. Alterations in mitochondrial-encoded genes contribute to defective OXPHOS, metabolic reprogramming, increased ROS, apoptosis evasion, chemoresistance, and metastasis. MEGs therefore represent promising targets for diagnostic, prognostic, and therapeutic development, and emerging modalities such as mitochondrial gene editing, allotopic expression, and nanocarrier delivery offer potential pathways to precision mitochondrial oncology. The authors declare no competing interests in the original article (PMID: 42385482; DOI: 10.1016/j.bbrc.2026.154218). Detailed experimental results and clinical validation were not reported in the abstract.