Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle
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.
Authors
- Sheik Nadeem Elahee Doomun (ORCID: https://orcid.org/0000-0002-6384-859X)
- Darren C. Henstridge (ORCID: https://orcid.org/0000-0003-4988-767X)
- Luke E. Formosa (ORCID: https://orcid.org/0000-0002-7740-6151)
- Simon Crawford (ORCID: https://orcid.org/0000-0002-6740-8743)
- Georg Ramm (ORCID: https://orcid.org/0000-0003-3596-2288)
- Danielle L. Rudler (ORCID: https://orcid.org/0000-0002-5540-6548)
- Kevin H. Liu
- Peter J. Meikle (ORCID: https://orcid.org/0000-0002-2593-4665)
- Haoyun Fang (ORCID: https://orcid.org/0000-0001-6582-1975)
- Artika P. Nath (ORCID: https://orcid.org/0000-0002-5688-2941)
- David W. Greening (ORCID: https://orcid.org/0000-0001-7516-485X)
- Thy Duong (ORCID: https://orcid.org/0000-0002-2521-078X)
- Kevin Huynh (ORCID: https://orcid.org/0000-0001-6170-2207)
- Aleksandra Filipovska (ORCID: https://orcid.org/0000-0002-6998-8403)
- Anna C. Calkin (ORCID: https://orcid.org/0000-0002-9861-0602)
- Michael Inouye (ORCID: https://orcid.org/0000-0001-9413-6520)
- Sergio Ruiz‐Carmona (ORCID: https://orcid.org/0000-0003-4920-5915)
- Brian G. Drew (ORCID: https://orcid.org/0000-0002-7839-9467)
- Simon T. Bond (ORCID: https://orcid.org/0000-0003-1551-8614)
- Shannen Walker (ORCID: https://orcid.org/0000-0001-5635-9184)
- E. King (ORCID: https://orcid.org/0000-0002-4950-5662)
- David P. De Souza (ORCID: https://orcid.org/0000-0002-7225-2632)
- Aaron W Jurrjens (ORCID: https://orcid.org/0000-0003-2349-4122)
- Aowen Zhuang
- Yingying Liu (ORCID: https://orcid.org/0000-0002-6725-1475)
- Christine Yang (ORCID: https://orcid.org/0000-0003-2800-6159)
Institutions
- University of Tasmania (AU)
- Baker Heart and Diabetes Institute (AU)
- The University of Melbourne (AU)
- The Kids Research Institute Australia (AU)
- La Trobe University (AU)
- Princess Margaret Hospital for Children (AU)
- Queen Elizabeth II Medical Centre (AU)
- ARC Centre of Excellence in Synthetic Biology (AU)
- Baker Engineering (United States) (US)
- Monash University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-08
- DOI
- https://doi.org/10.1038/s41467-025-57299-3
- Citations
- 14
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- National Heart Foundation of Australia
- National Health and Medical Research Council