ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription

• Published in: Nature cell biology Vol. 25; no. 8; pp. 1111 - 1120
• Main Authors: Dai, Chuan-Yang, Ng, Chai Chee, Hung, Grace Ching Ching, Kirmes, Ina, Hughes, Laetitia A., Du, Yunguang, Brosnan, Christopher A., Ahier, Arnaud, Hahn, Anne, Haynes, Cole M., Rackham, Oliver, Filipovska, Aleksandra, Zuryn, Steven
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2023; Nature Publishing Group
• Subjects: 13/51; 14/35; 38/22; 38/39; 38/89; 631/45/147; 631/80/642/333; 64/11; 82/1; Assembly; Biomedical and Life Sciences; Cancer Research; Cell Biology; Damage; Deoxyribonucleic acid; Developmental Biology; DNA; DNA damage; DNA glycosylase; DNA helicase; DNA repair; Enzymatic activity; Gene expression; Genomes; Letter; Life Sciences; Mitochondria; Mitochondrial DNA; NTH1 protein; Repair; Stem Cells; Transcription factors
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-023-01192-y

The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete
1
, suggesting a life-long trade-off between these two processes. Here in
Caenorhabditis elegans
, we find that the bZIP transcription factor ATFS-1/Atf5 (refs.
2
,
3
) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.
Dai et al. show that the transcription factor ATFS-1 interferes with mitochondrial pre-initiation transcription complex assembly and promotes mitochondrial DNA repair, thereby reducing age-dependent mitochondrial DNA damage in
Caenorhabditis
elegans
.