A new agent in the matrix: PINK1's expanded role in mitochondrial surveillance and regulation.

The identification of pathogenic autosomal recessive mutations in the gene encoding the PINK1 kinase provided early evidence linking mitochondrial dysfunction to neurodegeneration - in this case Parkinson's Disease. PINK1 has since become synonymous with mitophagy, with the prevailing model proposing two alternative fates. The first being partial import - inner-membrane penetration of its transmembrane domain (TMD) followed by PARL-mediated cleavage and degradation. This happens in healthy mitochondria with a high membrane potential (ΔΨ) across the inner-membrane - required for passage of proteins into or across the inner-membrane. The second being surface stabilisation, Parkin activation and initiation of mitophagy upon membrane depolarisation. But what if PINK1 acts in active mitochondria as well? Our recent work identifies a third fate - matrix entry. The findings expand the biology of PINK1 beyond mitochondrial surveillance for quality control alone. They suggest an additional mitophagy-independent regulatory role within the matrix, which turns out to be governed by the unusual properties of its TMD for the conferral of a decisive conformational switch.