Polyphenols in mtDNA Repair, Mitochondrial Biogenesis, and Mitophagy: An Integrative Review

Mitochondrial dysfunction is a central hallmark of metabolic, hepatic, cardiovascular, and neurodegenerative diseases. Dietary polyphenols modulate mitochondrial pathways, but their integrated effects remain poorly appreciated. This narrative review synthesizes preclinical and clinical evidence on four polyphenols (resveratrol, epigallocatechin-3-gallate, quercetin, and oleuropein) and examines their mechanisms in mitochondrial biogenesis, mtDNA protection, and mitophagy. Experimental studies indicate that these compounds activate conserved adaptive pathways, including sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), AMP-activated protein kinase (AMPK), and PTEN-induced kinase 1 (PINK1) with Parkin, therapy enhancing mitochondrial biogenesis, reducing oxidative stress, and promoting selective removal of damaged mitochondria. Evidence from human studies suggests improvements in endothelial function and metabolic flexibility, although direct human mitochondrial assessments remain scarce. Overall, dietary polyphenols appear to support mitochondrial quality control across multiple organs through coordinated signaling mechanisms. Critical limitations include bioavailability constraints and a lack of mitochondrial biomarkers in most clinical studies. Future investigations should incorporate advanced phenotyping and improved formulations to clarify the therapeutic potential of polyphenols as targeted modulators of mitochondrial health.