Mitochondrial Dysfunction and Bioenergetic Instability in Cancer Pathogenesis: Systematic Review of Mitochondria-Targeted Therapeutic Approaches

Background: Mitochondrial dysfunction and bioenergetic instability play key roles in cancer pathogenesis. This study aimed to systematically evaluate the role of mitochondria-targeted interventions in breast, lung, and colorectal cancers. Methods: This systematic review followed PRISMA guidelines 2020. Databases searched included PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, from 2020 to 2026. Experimental in vitro, in vivo, ex vivo, and clinical studies evaluating mitochondrial pathways or mitochondria-targeted interventions in breast, lung, and colorectal cancers were included, while reviews, editorials, case reports, conference abstracts, and non-English studies were excluded. Risk of bias was assessed using the SYRCLE tool, Cochrane Risk of Bias 2.0, and evidence certainty GRADE framework. Results: Twelve studies meet the inclusion criteria. Findings demonstrated that mitochondrial dysfunction, including OXPHOS inhibition, electron transport chain disruption, mitochondrial membrane depolarization, and ROS overproduction, contributed to tumor progression, chemoresistance, and metastasis. Mitochondria-targeted interventions reduced cancer cell viability, induced apoptosis, and improved treatment response. Risk of bias across studies was moderate, and the certainty of evidence was determined based on the GRADE approach. Conclusion: This review highlights the critical role of mitochondrial dysfunction in cancer progression and the potential of mitochondria-targeted therapies. Future research should focus on clinical translation, combination therapies, and molecular profiling to optimize patient-specific mitochondrial-based interventions.