A Damage-Gated Small-Molecule Chimera Selectively Enhances Mitophagy by Coupling Dysfunctional Mitochondria to Autophagy

Mitophagy is a central mitochondrial quality-control pathway, and its pharmacological activation is considered to be geroprotective. However, its small-molecule activators act indirectly by perturbing metabolism or mitochondrial function, limiting selectivity and increasing toxicity. Here, we describe a chemical biology strategy for activating damage-responsive mitophagy using bifunctional small molecules that couple mitochondrial recognition to the recruitment of the autophagic machinery. We designed and synthesized a focused library of chimeric molecules and identified MG-1 as a lead compound. It had minimal effects on basal autophagy but markedly enhanced autophagic flux and mitochondrial clearance under conditions of mitochondrial stress. Biochemical analyses, together with fluorescence and electron microscopy, showed that MG-1 promotes lysosomal degradation of damaged mitochondria without acting as a direct mitochondrial uncoupler. MG-1 was well tolerated across experimental systems and improved locomotor performance in a zebrafish model of MPTP-induced mitochondrial dysfunction. These findings establish damage-gated small-molecule chimeras as a promising approach for selective control of mitochondrial quality.