Mitophagy Modulation as an Emerging Pharmacological Strategy for Mitochondrial and Neurodegenerative Disorders

ABSTRACT Mitochondrial quality control is increasingly recognised as a central determinant of neuronal survival, and mitophagy - the selective autophagic clearance of damaged mitochondria - sits at the centre of this system. Loss-of-function mutations in PINK1 and PRKN cause autosomal-recessive, early-onset Parkinson's disease, establishing that failure of this pathway is sufficient to cause neurodegeneration in humans, while impaired mitophagic flux is also documented in Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. This narrative review synthesises current evidence on the biology of mitophagy and its pharmacological modulation. We outline the ubiquitin-dependent PINK1–Parkin axis and the receptor-mediated (NIX/BNIP3L, BNIP3, FUNDC1) pathways, together with the counter-regulatory role of the deubiquitinase USP30, and then compare how the disease-specific triggers of the four major neurodegenerative disorders converge on a shared downstream sequence in which damaged mitochondria accumulate and release mitochondrial DNA and other damage-associated molecular patterns, activating NLRP3 inflammasome and cGAS–STING signalling. We then review the principal therapeutic classes under development: natural inducers (urolithin A, spermidine, resveratrol), NAD+ precursors (nicotinamide riboside, nicotinamide mononucleotide), mTOR inhibitors and caloric-restriction mimetics, small-molecule PINK1 and Parkin activators, USP30 inhibitors, and emerging gene- and organelle-based strategies. Human safety and target-engagement data are strongest for urolithin A and NAD+ precursors, whereas first-in-class molecules built directly on the PINK1–Parkin–USP30 machinery remain in early clinical development, and recent mechanistic work indicates that several reported activators may act in part by sensitising cells to mitochondrial stress rather than through direct target engagement. The principal translational obstacles are blood–brain barrier delivery, target selectivity, the absence of validated biomarkers of mitophagic flux in the living human brain, and the need to modulate mitophagy within a therapeutic window rather than maximally.