Basal mitophagy runs without PINK1

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

Thomas McWilliams, Alan Prescott, L. Montava-Garriga, G. Ball, F. Singh, E. Barini, Miratul Muqit, S.P. Brooks and Ian Ganley (last author), at the MRC Protein Phosphorylation and Ubiquitylation Unit and Dundee Imaging Facility, University of Dundee. Cell Metabolism 27(2):439–449.e5, February 2018 (a brief report). Europe PMC lists funding from the Wellcome Trust, the UK Medical Research Council and Parkinson's UK. The reporter mouse came from the same group in J Cell Biol 2016.

What happened

Mitophagy is the cell's disposal of damaged mitochondria. In dishes, PINK1 and parkin trigger it when mitochondria lose their charge (landmark 15). Whether this is how mitophagy works in a living animal was unknown.

The 2016 "mito-QC" mouse carries a mitochondrial marker that changes colour when it reaches the lysosome, so mitophagy can be counted in tissue. In the 2018 study, mitophagy was frequent in nigral dopamine neurons and in microglia. In nearly all tissues, deleting Pink1 left it unchanged, even though parkin activation after a mitochondrial poison failed in cells without PINK1. Pancreatic islets were the exception: there, loss of Pink1 did change basal mitophagy (the abstract does not give the direction). A fruit-fly study the same year, using fly reporters, also found little effect of losing Pink1 or parkin on basal mitophagy (Lee et al., J Cell Biol 2018).

Why it moved us toward a cure

It does not weaken the genetics: PINK1 and parkin mutations still cause Parkinson's. It does weaken the assumption that these genes work by driving routine mitophagy, which matters for the new mitophagy drugs (landmark 156). Such drugs may help only under stress, and other, undiscovered pathways run the baseline.

Outcome

Open. PINK1-dependent mitophagy under acute stress remains plausible. The authors concluded that multiple, still-undiscovered pathways run basal mitophagy. No correction or retraction was found for either paper. Later in vivo work on PINK1 was searched once and nothing that overturned this was found.

Sources

• McWilliams et al., "Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand," Cell Metab 2018;27:439–449.e5, DOI 10.1016/j.cmet.2017.12.008, PMID 29337137, PMC5807059
• McWilliams et al., J Cell Biol 2016, DOI 10.1083/jcb.201603039
• Lee et al., "Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin," J Cell Biol 2018;217:1613–1622, DOI 10.1083/jcb.201801044, PMID 29500189
• Not yet verified: group sizes for basal data and the percentage of dopamine neurons in mitophagy (not in the abstract); later counter-evidence beyond one search.