Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle

Simon T. Bond, Emily J. King, Shannen M. Walker, Christine Yang, Yingying Liu, Kevin H. Liu, Aowen Zhuang, Aaron W. Jurrjens, Haoyun A. Fang, Luke E. Formosa, Artika P. Nath, Sergio Ruiz Carmona, Michael Inouye, Thy Duong, Kevin Huynh, Peter J. Meikle, Simon Crawford, Georg Ramm, Sheik Nadeem Elahee Doomun, David P. Souza, Danielle L. Rudler, Anna C. Calkin, Aleksandra Filipovska, David W. Greening, Darren C. Henstridge and Brian G. Drew ()
Additional contact information
Simon T. Bond: Baker Heart & Diabetes Institute
Emily J. King: Baker Heart & Diabetes Institute
Shannen M. Walker: Baker Heart & Diabetes Institute
Christine Yang: Baker Heart & Diabetes Institute
Yingying Liu: Baker Heart & Diabetes Institute
Kevin H. Liu: Baker Heart & Diabetes Institute
Aowen Zhuang: Baker Heart & Diabetes Institute
Aaron W. Jurrjens: Baker Heart & Diabetes Institute
Haoyun A. Fang: Baker Heart & Diabetes Institute
Luke E. Formosa: Monash University
Artika P. Nath: Baker Heart & Diabetes Institute
Sergio Ruiz Carmona: Baker Heart & Diabetes Institute
Michael Inouye: Baker Heart & Diabetes Institute
Thy Duong: Baker Heart & Diabetes Institute
Kevin Huynh: Baker Heart & Diabetes Institute
Peter J. Meikle: Baker Heart & Diabetes Institute
Simon Crawford: Monash University
Georg Ramm: Monash University
Sheik Nadeem Elahee Doomun: Bio21
David P. Souza: Bio21
Danielle L. Rudler: Western Australia
Anna C. Calkin: Baker Heart & Diabetes Institute
Aleksandra Filipovska: Western Australia
David W. Greening: Baker Heart & Diabetes Institute
Darren C. Henstridge: Baker Heart & Diabetes Institute
Brian G. Drew: Baker Heart & Diabetes Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is known to be activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for activation of the mtISR remain mostly unknown. A gene often associated with mtDNA mutations/deletions is Polg1, which encodes the mitochondrial DNA Polymerase γ (PolG). Here, we describe an inducible, tissue specific model of PolG mutation, which in muscle specific animals leads to rapid development of mitochondrial dysfunction and muscular degeneration in male animals from ~5 months of age. Detailed molecular profiling demonstrated robust activation of the mtISR in muscles from these animals. This was accompanied by striking alterations to enzymes in the mitochondrial folate cycle that was likely driven by a specific depletion in the folate cycle metabolite 5,10 methenyl-THF, strongly implying imbalanced folate intermediates as a previously unrecognised pathology linking the mtISR and mitochondrial disease.

Date: 2025
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DOI: 10.1038/s41467-025-57299-3

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