Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle
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....
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57299-3 |
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| author | 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. de Souza Danielle L. Rudler Anna C. Calkin Aleksandra Filipovska David W. Greening Darren C. Henstridge Brian G. Drew |
| author_facet | 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. de Souza Danielle L. Rudler Anna C. Calkin Aleksandra Filipovska David W. Greening Darren C. Henstridge Brian G. Drew |
| author_sort | Simon T. Bond |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-345a906e47c24af198ae8e2c6ca1d92f |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-345a906e47c24af198ae8e2c6ca1d92f2025-08-20T02:59:54ZengNature PortfolioNature Communications2041-17232025-03-0116112110.1038/s41467-025-57299-3Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycleSimon T. Bond0Emily J. King1Shannen M. Walker2Christine Yang3Yingying Liu4Kevin H. Liu5Aowen Zhuang6Aaron W. Jurrjens7Haoyun A. Fang8Luke E. Formosa9Artika P. Nath10Sergio Ruiz Carmona11Michael Inouye12Thy Duong13Kevin Huynh14Peter J. Meikle15Simon Crawford16Georg Ramm17Sheik Nadeem Elahee Doomun18David P. de Souza19Danielle L. Rudler20Anna C. Calkin21Aleksandra Filipovska22David W. Greening23Darren C. Henstridge24Brian G. Drew25Baker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBiochemistry and Molecular Biology, Monash UniversityBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteMonash Ramaciotti Centre for Cryo Electron Microscopy, Monash UniversityBiochemistry and Molecular Biology, Monash UniversityMetabolomics Australia, Bio21Metabolomics Australia, Bio21ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Western AustraliaBaker Heart & Diabetes InstituteARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Western AustraliaBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteBaker Heart & Diabetes InstituteAbstract 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.https://doi.org/10.1038/s41467-025-57299-3 |
| spellingShingle | 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. de Souza Danielle L. Rudler Anna C. Calkin Aleksandra Filipovska David W. Greening Darren C. Henstridge Brian G. Drew Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle Nature Communications |
| title | Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle |
| title_full | Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle |
| title_fullStr | Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle |
| title_full_unstemmed | Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle |
| title_short | Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle |
| title_sort | mitochondrial damage in muscle specific polg mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle |
| url | https://doi.org/10.1038/s41467-025-57299-3 |
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