Transmembrane Parkinson's disease mutation of PINK1 leads to altered mitochondrial anchoring

Raelynn Brassard; Elena Arutyunova; Emmanuella Takyi; L Michel Espinoza-Fonseca; Howard S Young; Nicolas Touret; M Joanne Lemieux

doi:10.1016/j.jbc.2025.108253

Transmembrane Parkinson's disease mutation of PINK1 leads to altered mitochondrial anchoring

J Biol Chem. 2025 Feb 3;301(3):108253. doi: 10.1016/j.jbc.2025.108253. Online ahead of print.

Authors

Raelynn Brassard¹, Elena Arutyunova¹, Emmanuella Takyi², L Michel Espinoza-Fonseca³, Howard S Young⁴, Nicolas Touret⁵, M Joanne Lemieux⁶

Affiliations

¹ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
² Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
³ Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
⁵ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address: touret@ualberta.ca.
⁶ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada. Electronic address: mlemieux@ualberta.ca.

Abstract

Parkinson's disease is a devastating neurodegenerative disease resulting from the death of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Familial and sporadic forms of the disease have been linked to mitochondrial dysfunction. Pathology has been identified with mutations in the PARK6 gene encoding PTEN-induced kinase 1 (PINK1), a quality control protein in the mitochondria. Disease-associated mutations at the transmembrane (TM) region of PINK1 protein were predicted to disrupt the cleavage of the TM region by the PARL (presenilin-associated rhomboid-like) protease at the inner mitochondrial membrane. Here, using microscopy, kinetic analysis, and molecular dynamics simulations, we analyzed three Parkinson's disease-associated TM mutations; PINK1-C92F, PINK1-R98W, and PINK1-I111S, and found that mitochondrial localization and cleavage by the PARL protease were not significantly impaired. However, clearance of hydrolyzed PINK1-R98W appears to be compromised because of altered positioning of the protein in the outer mitochondrial membrane, preventing association with translocase of the outer membrane complexes and slowing cleavage by PARL. This single amino acid change slows degradation of proteolyzed PINK1, increasing its accumulation at the outer mitochondrial membrane and resulting in increased mitophagy and decreased mitochondrial content among these cells.

Keywords: MD simulation; PARL; Parkinson’s disease; proteostasis; rhomboid protease.