bims-mitpro 2024-04-14 papers

Issue of 2024‒04‒14
two papers selected by
Andreas Kohler, Umeå University

Autophagy. 2024 Apr 10.

MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.

Mohamed A Eldeeb, Armaan Fallahi, Andrea Soumbasis, Andrew N Bayne, Jean-François Trempe, Edward A Fon.

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; PINK1; Parkinson’s disease; mitochondrial quality control; mitophagy

DOI: https://doi.org/10.1080/15548627.2024.2340399

Mol Neurobiol. 2024 Apr 06.

Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.

Sarah Hui, Jimmy George, Minesh Kapadia, Hien Chau, Zahn Bariring, Rebecca Earnshaw, Kashfia Shafiq, Lorraine V Kalia, Suneil K Kalia.

Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration.

Keywords: Alpha-synuclein; Lysosomes; Mitochondria dysfunction; Mitophagy; Neurodegeneration; Parkinson’s disease; Substantia nigra pars compacta

DOI: https://doi.org/10.1007/s12035-024-04131-6