RRC ID 53262
Author Lin YF, Schulz AM, Pellegrino MW, Lu Y, Shaham S, Haynes CM.
Title Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response.
Journal Nature
Abstract Mitochondrial genomes (mitochondrial DNA, mtDNA) encode essential oxidative phosphorylation (OXPHOS) components. Because hundreds of mtDNAs exist per cell, a deletion in a single mtDNA has little impact. However, if the deletion genome is enriched, OXPHOS declines, resulting in cellular dysfunction. For example, Kearns-Sayre syndrome is caused by a single heteroplasmic mtDNA deletion. More broadly, mtDNA deletion accumulation has been observed in individual muscle cells and dopaminergic neurons during ageing. It is unclear how mtDNA deletions are tolerated or how they are propagated in somatic cells. One mechanism by which cells respond to OXPHOS dysfunction is by activating the mitochondrial unfolded protein response (UPR(mt)), a transcriptional response mediated by the transcription factor ATFS-1 that promotes the recovery and regeneration of defective mitochondria. Here we investigate the role of ATFS-1 in the maintenance and propagation of a deleterious mtDNA in a heteroplasmic Caenorhabditis elegans strain that stably expresses wild-type mtDNA and mtDNA with a 3.1-kilobase deletion (∆mtDNA) lacking four essential genes. The heteroplasmic strain, which has 60% ∆mtDNA, displays modest mitochondrial dysfunction and constitutive UPR(mt) activation. ATFS-1 impairment reduced the ∆mtDNA nearly tenfold, decreasing the total percentage to 7%. We propose that in the context of mtDNA heteroplasmy, UPR(mt) activation caused by OXPHOS defects propagates or maintains the deleterious mtDNA in an attempt to recover OXPHOS activity by promoting mitochondrial biogenesis and dynamics.
Volume 533(7603)
Pages 416-9
Published 2016-5-19
DOI 10.1038/nature17989
PII nature17989
PMID 27135930
PMC PMC4873342
MeSH Animals Caenorhabditis elegans / cytology* Caenorhabditis elegans / genetics* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism DNA, Mitochondrial / genetics Gene Deletion Genes, Essential / genetics Genome, Mitochondrial / genetics* Mitochondria / genetics* Mitochondria / metabolism* Mitochondria / pathology Organelle Biogenesis Oxidative Phosphorylation Transcription Factors / metabolism Ubiquitin-Protein Ligases / metabolism Unfolded Protein Response / physiology*
IF 42.779
Times Cited 99
C.elegans tm4919 tm1779 tm598