Journal Article

Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response

Lin, Yi-Fan, Lu, Yun, Pellegrino, Mark W., Shaham, Shai, Haynes, Cole M., Schulz, Anna M.

2016

Overview

In the context of mitochondrial genome heteroplasmy that causes defective oxidative phosphorylation in C. elegans , the ATFS-1-mediated mitochondrial unfolded protein response maintains the deleterious mitochondrial DNA in an attempt to recover oxidative phosphorylation activity and avoid cellular dysfunction. Mitochondrial mutations tolerated — up to a point A eukaryotic cell contains a single copy of the nuclear genome, but hundreds of mitochondrial genomes (mtDNA), encoding proteins essential for oxidative phosphorylation. The cell can tolerate a number of mutations or deletions in mitochondrial genes, but beyond a toxic threshold, further mutations can cause inborn mitochondrial diseases. Cole Haynes and colleagues examined the mechanism by which mtDNA mutations are tolerated by focusing on the role of the mitochondrial unfolded protein response (UPR mt ), a process mediated by the transcription factor ATFS-1 that promotes the recovery of defective mitochondria. They compare normal Caenorhabditis elegans roundworms to a heteroplasmic strain carrying a deletion mutation in four mitochondrial-encoded genes in 60% of the mitochondria. The heteroplasmic strain displayed constant UPR mt activation and only modest mitochondrial dysfunction. In worms with impaired UPR mt activity, there was a tenfold reduction in the number of mutated mtDNAs. The authors infer that ATFS-1-mediated UPR mt maintains the deleterious mtDNA in an attempt to recover oxidative phosphorylation activity, to avoid the possible alternative scenario of the demise of the cell. 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 1 and dopaminergic neurons 2 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 3 , 4 . 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 5 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 13/89 / 14/34 / 14/35 / 14/63 / 38/22 / 38/90 / 45/61 / 49/47 / 631/80/642/333 / 631/80/86/2366 / 64/11 / Animals / Autophagy / Biosynthesis / Caenorhabditis elegans - cytology / Caenorhabditis elegans - genetics / Caenorhabditis elegans Proteins - genetics / Caenorhabditis elegans Proteins - metabolism / Cell division / DNA, Mitochondrial - genetics / Gene Deletion / Genes, Essential - genetics / Genetic research / Genome, Mitochondrial - genetics / Genomes / Genomics / Humanities and Social Sciences / Kinases / letter / Mitochondria / Mitochondria - genetics / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial DNA / multidisciplinary / Mutation / Organelle Biogenesis / Oxidative Phosphorylation / Physiological aspects / Proteins / Science / Transcription Factors - metabolism / Ubiquitin-Protein Ligases - metabolism / Unfolded Protein Response - physiology