Ginsenoside Re binds Drp1 Leu94 across species to restore mitochondrial homeostasis via Atg1/ULK1-dependent fission-mitophagy coupling in age-related degeneration

Aging profoundly impacts the brain, serving as a primary driver of neurodegenerative diseases through mechanisms closely linked to mitochondrial dysfunction. Despite its clinical significance, the molecular mechanisms remain unclear, and safe, effective therapies are urgently needed. Here, leveraging ginseng's neuroprotective potential, we screened for blood-brain barrier-permeable saponins with optimal neuroprotective efficacy and identified ginsenoside Re (Re) as the predominant mitochondrially targeted neuroprotective saponin. Midlife Reintervention, temporally aligned with the natural window of mitochondrial hyperfusion, rescued age-related degenerative pathology in Drosophila. Re administration ameliorated dopaminergic neuron loss, mitigated muscles pathology, improved cognitive-motor deficits, and extended healthspan. Mechanistic studies revealed that Re directly binds to the Drp1 across multiple species via the highly conserved L94 residue, triggering robust S616 phosphorylation that drives Drp1 translocation to mitochondria, thereby restoring fission-fusion equilibrium. Re further spatiotemporally coupled fission-mitophagy through the Drp1-Atg1/ULK1 axis, enabling autophagosome initiation and ensuring efficient clearance of damaged organelles. This dual regulation enhanced bioenergetic capacity and delayed functional decline. Genetic ablation of Drp1 L94 completely abolished Re's benefits, while translational studies in mice confirmed that healthspan extension required intact Drp1-L94 functionality. Notably, Re demonstrated conserved neuroprotective efficacy in both human induced pluripotent stem cells-derived dopaminergic neurons and Drosophila Parkinson's model, indicating preservation of the Drp1-mitophagy pathway across species. Our findings establish Re as a geroprotector that targets the conserved Drp1-L94 residue to restore mitochondrial homeostasis. By spatiotemporally coupling fission to Atg1-mediated mitophagy during the critical midlife hyperfusion window, Re delays neurodegeneration, thereby establishing a molecular basis for developing therapies against age-related decline.