PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome

• Published in: Cell reports (Cambridge) Vol. 35; no. 9; p. 109203
• Main Authors: Ahier, Arnaud, Dai, Chuan-Yang, Kirmes, Ina, Cummins, Nadia, Hung, Grace Ching Ching, Götz, Jürgen, Zuryn, Steven
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2021
• Subjects: Alzheimer's disease; Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans Proteins - metabolism; DNA, Mitochondrial - genetics; Genome, Mitochondrial; Heteroplasmy; mitochondria; mitophagy; Mitophagy - genetics; mtDNA; Muscle Cells - metabolism; Neurons - metabolism; parkin; PINK1; polyglutamate; Protein Serine-Threonine Kinases - metabolism; proteotoxicity; tau; Ubiquitin-Protein Ligases - metabolism; heteroplasmy; mitophagy; PINK1; parkin; mtDNA; mitochondria; tau; Alzheimer's disease; proteotoxicity; polyglutamate
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109203

In multiple species, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, but the mechanisms that drive these heteroplasmy differences are unknown. We find that the conserved PTEN-induced putative kinase (PINK1/PINK-1) and the E3 ubiquitin-protein ligase parkin (PDR-1), which are required for mitochondrial autophagy (mitophagy), underlie stereotyped differences in heteroplasmy of a deleterious mitochondrial genome mutation (ΔmtDNA) between major somatic tissues types in Caenorhabditis elegans. We demonstrate that tissues prone to accumulating ΔmtDNA have lower mitophagy responses than those with low mutation levels. Moreover, we show that ΔmtDNA heteroplasmy increases when proteotoxic species that are associated with neurodegenerative disease and mitophagy inhibition are overexpressed in the nervous system. These results suggest that PINK1 and parkin drive organism-wide patterns of heteroplasmy and provide evidence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons. [Display omitted] •Tissue-specific mtDNA mutation levels are determined by Pink1 and parkin activity•Tissues prone to accumulating mtDNA mutations have lower mitophagy levels•Proteotoxic Tau and polyQ repeats cause increased mtDNA mutation levels in neurons In animals, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, but the mechanisms that drive these differences are unknown. Ahier et al. show that the activities of Pink1 and parkin determine mtDNA mutation levels in major somatic tissues in C. elegans.