MITOCHONDRIAL PHARMACOLOGY IN AGING AND DISEASE: MOLECULAR TARGETS, THERAPEUTIC STRATEGIES AND TRANSLATIONAL CHALLENGES

Udutha Sheethal*, D. Harshitha, K. Poojitha, K. Venkata Lakshmi, A. Namitha, C. Priya

In addition to producing energy, mitochondria influence innate immunological detection, calcium handling, redox signaling, and a cell's choice to survive or die. They are currently thought to be a contributing factor to aging, neurological, cardiovascular, metabolic, and cancerous diseases. In this review, we outline the several mechanisms that lead to mitochondrial dysfunction, including inadequate biogenesis, an imbalance between fission and fusion, deficient mitophagy, oxidative stress, telomere-linked signaling, and leakage of mitochondrial DNA. We also link each process to the medications that affect it. Respiratory-chain modulators, antioxidants that target mitochondria, metabolite-carrier modulators and insulin sensitizers, inducers of biogenesis (such as AMP-activated protein kinase activators, nicotinamide adenine dinucleotide precursors, and peroxisome proliferator-activated receptor agonists), regulators of mitochondrial dynamics, mild uncouplers, inhibitors of mitochondrial translation, and modulators of mitophagy and senescence. We also discuss genetic editing, diet, exercise, and mitochondrial transplantation. Clinical trials have yielded inconsistent results, while animal results are frequently impressive. The field is hampered by poor delivery to the organelle, species variations, reliance on surrogate end points, patient variability, and a lack of validated biomarkers. Biomarker-based patient selection, improved delivery chemistry, and thoughtful combination therapy will likely be key components of future advancements.