Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis Journal Article

   


Authors: Fu, Y.; Sacco, O.; DeBitetto, E.; Kanshin, E.; Ueberheide, B.; Sfeir, A.
Article Title: Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis
Abstract: Mitochondrial DNA double-strand breaks (mtDSBs) lead to the degradation of circular genomes and a reduction in copy number; yet, the cellular response in human cells remains elusive. Here, using mitochondrial-targeted restriction enzymes, we show that a subset of cells with mtDSBs exhibited defective mitochondrial protein import, reduced respiratory complexes, and loss of membrane potential. Electron microscopy confirmed the altered mitochondrial membrane and cristae ultrastructure. Intriguingly, mtDSBs triggered the integrated stress response (ISR) via the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by DELE1 and heme-regulated eIF2α kinase (HRI). When ISR was inhibited, the cells experienced intensified mitochondrial defects and slower mtDNA recovery post-breakage. Lastly, through proteomics, we identified ATAD3A—a membrane-bound protein interacting with nucleoids—as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. In summary, our study delineates the cascade connecting damaged mitochondrial genomes to the cytoplasm and highlights the significance of the ISR in maintaining mitochondrial homeostasis amid genome instability. © 2023 Elsevier Inc.
Keywords: mitochondrial dna; double-strand breaks; protein import; integrated stress response; atad3a
Journal Title: Molecular Cell
Volume: 83
Issue: 20
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2023-10-19
Start Page: 3740
End Page: 3753.e9
Language: English
DOI: 10.1016/j.molcel.2023.09.026
PUBMED: 37832546
PROVIDER: scopus
PMCID: PMC11229056
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85174188592&doi=10.1016%2fj.molcel.2023.09.026&partnerID=40&md5=60ab5fabb39d6c3106b18e40e19866cf
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Agnel Sfeir -- Source: Scopus
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MSK Authors
  1. Agnel Sfeir
    16 Sfeir
  2. Olivia Sacco
    4 Sacco
  3. Emily Debitetto
    2 Debitetto
  4. Yi Fu
    3 Fu
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