Mitochondrial import stress and PINK1-mediated mitophagy: the role of the PINK1-TOMM-TIMM23 supercomplex

ABSTRACT

Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.

KEYWORDS:

• Mitochondrial import
• mitochondrial quality control
• mitophagy
• Parkinson’s disease
• PINK1

Acknowledgements

M.A.E. is a Canadian Institutes of Health Research (CIHR) Banting Fellow and was supported by Parkinson Canada. A.N.B. was supported by a CIHR Doctoral Fellowship and a Centre de Recherche en Biologie Structurale (CRBS) Maximilian Eivaskhani in Memoriam Graduate Studentship. E.A.F. holds a Canada Research Chair 1315 (Tier 1) in Parkinson’s disease (#950-232176), and J.-F.T. holds a Canada Research Chair (Tier 2) in Structural Pharmacology (#950-229792).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research work was funded by a Michael J. Fox Foundation grant [#18293] to J.-F.T. and E.A.F., as well as a CIHR Foundation grant [FDN-154301] to E.A.F. and a CIHR Project grant [PJT-186189] to J.-F.T.