PINK1 and the mitophagy pathway

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Enza Maria Valente (Mendel Institute, Rome), Patrick Abou-Sleiman, Nicholas Wood (London) and 19 co-authors. Later pathway work by Derek Narendra and Richard Youle (US National Institutes of Health). Funders were not checked.

What happened

Valente et al. found two homozygous mutations in the kinase domain of PINK1 (a truncating one and a missense one at a conserved position) in three consanguineous families with the PARK6 form of early-onset recessive Parkinson's. Cell studies suggested PINK1 sits in mitochondria and protects cells from stress, which the mutations abolish. Science 304:1158–1160 (online 15 April 2004). Narendra et al. then showed that parkin (landmark 12) is recruited to damaged, depolarised mitochondria and promotes their removal by autophagy ("mitophagy"). J Cell Biol 183:795–803, 2008.

Why it moved us toward a cure

It connected the genetic cause directly to the mitochondrial failure suggested by landmarks 11 and 13, and gave drug targets: PINK1/parkin activators and USP30 inhibitors (USP30 opposes parkin signalling).

Outcome

Open. Mission Therapeutics' USP30 inhibitor MTX325 is in a Phase 1 trial (NCT07630545, started 30 Nov 2023, estimated 106 people): parts 1–4 in healthy volunteers are complete and part 5, multiple doses in people with Parkinson's, was in progress when the record was last updated (Sept 2026; primary completion estimated June 2027). In October 2025 the company said it raised $13.3 million, that CSF sampling and PET showed brain penetration in Phase Ia, and that a $5.2 million grant from the Michael J. Fox Foundation and Parkinson's UK supports development; it expects proof-of-mechanism data in the second half of 2027. There is no efficacy data. In October 2023 AbbVie bought Mitokinin, whose lead compound is a PINK1 activator, for $110 million upfront and up to $545 million in milestones; AbbVie's release called the programme discovery-stage and no trial of that compound was confirmed (AbbVie's ABBV-1088 Phase 1 trials are registered, but the sources read do not say it is the Mitokinin compound).

Sources

• Valente et al., Science 2004, DOI 10.1126/science.1096284 (citation via Alzforum)
• Narendra et al., J Cell Biol 2008, DOI 10.1083/jcb.200809125 (PMC2592826)
• ClinicalTrials.gov NCT07630545 (MTX325-101, sponsor Mission Therapeutics)
• Mission Therapeutics, 15 Oct 2025 financing release (company claims; no peer review)
• AbbVie release, 5 Oct 2023 (deal terms; funding fact only) · NCT06414798, NCT06579300 (ABBV-1088)
• Not yet verified: the later PINK1-upstream-of-parkin papers (not read; the prose claims only the 2008 Narendra paper); whether ABBV-1088 is the Mitokinin PINK1 activator; the exact PINK1 families' origins.