Mitochondrial Dysfunction in Cellular Aging: From Molecular Mechanisms to Emerging Therapeutic Strategies

This comprehensive review examines the critical role of mitochondrial dysfunction(definition) in cellular aging and the pathogenesis of age-related diseases. It begins by detailing methodological approaches for studying aged mitochondria, outlining in vitro senescence(definition) models such as replicative, therapy-induced, and stress-induced premature senescence. Key assays for characterizing the senescent phenotype are discussed, emphasizing the importance of measuring mitochondrial morphology, membrane potential, and reactive oxygen species (ROS) generation. The article critically analyzes therapeutic strategies aimed at correcting mitochondrial failures, with a strong focus on antioxidant interventions. It compares the endogenous electron carrier Coenzyme Q10 with MitoQ, an engineered derivative that utilizes a lipophilic cation for targeted accumulation within the mitochondrial matrix. Clinical and preclinical evidence demonstrates MitoQ's superior efficacy in reducing oxidative stress and improving cardiovascular and skeletal muscle function. Additionally, the review addresses the biological challenges of mitochondrial DNA (mtDNA) mutations and heteroplasmy. It traces the development of mtDNA editing technologies from early protein-based nucleases, such as MitoTALENs and MitoZFNs, to revolutionary CRISPR-free base editors like DdCBEs and TAMs, which allow for precise nucleotide conversions without inducing double-strand breaks. The transition from bench to bedside is evaluated through the safety and tolerability profiles of leading mitochondrial-targeted compounds, including Elamipretide, Urolithin A, and C458. The text highlights how these interventions target specific pathways like mitophagy induction and mitochondrial stress responses. Finally, the article explores the convergent pathophysiology of neurodegenerative and metabolic disorders, identifying shared mechanisms such as metabolic reprogramming, reverse electron transport at Complex I, and the p53-PGC-1α signaling axis. By integrating diagnostic methodologies, genetic editing advancements, and pharmacological interventions, this review provides a foundational framework for future gerotherapeutic research aimed at mitigating age-related functional decline. Source: https://www.regenmedsci.com/posts/mitochondrial-dysfunction-in-cellular-aging-from-molecular-mechanisms-to-emerging-therapeutic-strategies