DNA damage response regulator ATR licenses PINK1-mediated mitophagy

Defective DNA damage response (DDR) and mitochondrial dysfunction are a major etiology of tissue impairment and aging. Mitochondrial autophagy (mitophagy) is a mitochondrial quality control (MQC) mechanism to selectively eliminate dysfunctional mitochondria. ATR (ataxia-telangiectasia and Rad3-related) is a key DDR regulator playing a pivotal role in DNA replication stress response and genomic stability. Paradoxically, the human Seckel syndrome caused by ATR mutations exhibits premature aging and neuropathies, suggesting a role of ATR in nonreplicating tissues. Here, we report a previously unknown yet direct role of ATR at mitochondria. We find that ATR and PINK1 (PTEN-induced kinase 1) dock at the mitochondrial translocase TOM/TIM complex, where ATR interacts directly with and thereby stabilizes PINK1. ATR deletion silences mitophagy initiation thereby altering oxidative phosphorylation functionality resulting in reactive oxygen species overproduction that attack cytosolic macromolecules, in both cells and brain tissues, prior to nuclear DNA. This study discloses ATR as an integrated component of the PINK1-mediated MQC program to ensure mitochondrial fitness. Together with its DDR function, ATR safeguards mitochondrial and genomic integrity under physiological and genotoxic conditions.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-02-27
DOI
https://doi.org/10.1093/nar/gkaf178
Citations
4
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
3.22

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article

DNA damage response regulator ATR licenses PINK1-mediated mitophagy

Murat Kirtay, Joanna Kirkpatrick, Kanstantsin Siniuk, Xiaobing Qing et al.
4 citations
Nucleic Acids Research
Mitochondrial Function and Pathology
3.22
article

DNA damage response regulator ATR licenses PINK1-mediated mitophagy

Murat Kirtay, Joanna Kirkpatrick, Kanstantsin Siniuk, Xiaobing Qing, Marco Foiani, Christian Marx, Galina V. Beznoussenko, Gururaj Rao Kidiyoor, Philipp Koch, Katrin Buder, Xingzhi Xu, Christopher Bruhn, Martin Westermann, Yamin Gong, Eric J. Brown, Zhao‐Qi Wang
article en
4 citations

Abstract

Defective DNA damage response (DDR) and mitochondrial dysfunction are a major etiology of tissue impairment and aging. Mitochondrial autophagy (mitophagy) is a mitochondrial quality control (MQC) mechanism to selectively eliminate dysfunctional mitochondria. ATR (ataxia-telangiectasia and Rad3-related) is a key DDR regulator playing a pivotal role in DNA replication stress response and genomic stability. Paradoxically, the human Seckel syndrome caused by ATR mutations exhibits premature aging and neuropathies, suggesting a role of ATR in nonreplicating tissues. Here, we report a previously unknown yet direct role of ATR at mitochondria. We find that ATR and PINK1 (PTEN-induced kinase 1) dock at the mitochondrial translocase TOM/TIM complex, where ATR interacts directly with and thereby stabilizes PINK1. ATR deletion silences mitophagy initiation thereby altering oxidative phosphorylation functionality resulting in reactive oxygen species overproduction that attack cytosolic macromolecules, in both cells and brain tissues, prior to nuclear DNA. This study discloses ATR as an integrated component of the PINK1-mediated MQC program to ensure mitochondrial fitness. Together with its DDR function, ATR safeguards mitochondrial and genomic integrity under physiological and genotoxic conditions.

Nucleic Acids ResearchVol. 53(5)
Shandong University (CN), Shenzhen University (CN), University of Milan (IT), IFOM (IT), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE), Jena University Hospital (DE), State Key Laboratory of Microbial Technology, Friedrich Schiller University Jena (DE), University of Pennsylvania (US), Paul Ehrlich Institut (DE)
Shandong University, Deutsche Forschungsgemeinschaft, German-Israeli Foundation for Scientific Research and Development, Leibniz-Gemeinschaft
Openalex Percentile: Top 9%
Mitochondrial Function and Pathology
3.22
DOIOpen Access PDFOpenAlex
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