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

Nature volume 533, pages 416419 (19 May 2016) | Download Citation


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 cells1 and dopaminergic neurons2 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 (UPRmt), a transcriptional response mediated by the transcription factor ATFS-1 that promotes the recovery and regeneration of defective mitochondria3,4. 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 genes5. The heteroplasmic strain, which has 60% mtDNA, displays modest mitochondrial dysfunction and constitutive UPRmt activation. ATFS-1 impairment reduced the mtDNA nearly tenfold, decreasing the total percentage to 7%. We propose that in the context of mtDNA heteroplasmy, UPRmt activation caused by OXPHOS defects propagates or maintains the deleterious mtDNA in an attempt to recover OXPHOS activity by promoting mitochondrial biogenesis and dynamics.

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Gene Expression Omnibus

Data deposits

The microarray data have been deposited in a MIAME-compliant format to the Gene Expression Omnibus database under accession number GSE73669.


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We thank B. Lemire, the National Bioresource Project and the Caenorhabditis Genetics Center for providing C. elegans strains (funded by NIH Office of Research 362 Infrastructure Programs (P40 OD010440), and the Genomics and Bioinformatics Facilities at Memorial Sloan Kettering Cancer Center). This work was supported by National Institutes of Health grants (R01AG040061 and R01AG047182) to C.M.H. and (R01HD078703 and R01NS081490) to S.S., and a Parkinson’s Disease Foundation grant (PDF-FBS-1314) to Y.-F.L. and Deutsche Forschungsgemeinschaft (DFG, SCHU 3023/1-1) to A.M.S.

Author information


  1. Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Yi-Fan Lin
    • , Anna M. Schulz
    • , Mark W. Pellegrino
    •  & Cole M. Haynes
  2. Laboratory of Developmental Genetics, The Rockefeller University, New York, New York 10065, USA

    • Yun Lu
    •  & Shai Shaham
  3. BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA

    • Cole M. Haynes


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Y.-F.L. and C.M.H. planned the experiments. Y.-F.L. generated the worm strains and performed the mtDNA quantification and obtained the images. A.M.S. and Y.-F.L. performed the oxygen consumption analysis and M.W.P. performed the microarray experiments. Electron microscopy was performed by Y.Lu under the supervision of S.S. Y.-F.L. and C.M.H. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Cole M. Haynes.

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  1. 1.

    Supplementary Tables

    This file contains Supplementary Tables 1-2 comprising: (1) the relative fold induction and P values for each mRNA and (2) list of Primers that specifically amplify wild-type or ΔmtDNA .

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