title: Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response.
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.
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Schulz
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Pellegrino
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Shai
authors.initials: S
authors.lastname: Shaham
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Cole M
authors.initials: CM
authors.lastname: Haynes
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D017353:Gene Deletion; D020043:Genes, Essential / Q000235:genetics; D054629:Genome, Mitochondrial / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001678:Organelle Biogenesis; D010085:Oxidative Phosphorylation; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C548052:ATFS-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D004272:DNA, Mitochondrial; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein