ArticleNature communications2025
Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Small molecules rescue pathogenic POLGA aggregation and restore its functions in a mouse model of PEO.EMBO molecular medicine · 2026Article
- Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.Science advances · 2026Article
- Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.HGG advances · 2026Article
- Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.Muscles (Basel, Switzerland) · 2026Review
- Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.iScience · 2026Article
- Comparative analysis of muscle pathologies and metabolic signaling in mouse models of mitochondrial dysfunction.Scientific reports · 2026Article
- Model organisms in POLG-related disorders: insights from yeast to multicellular systems.Cell death & disease · 2025Review
- Folic acid ameliorates placental structure and function in fetal growth restriction via epigenetic modifications.Clinical epigenetics · 2025Article
- Ubiquitous Expression ofLife (Basel, Switzerland) · 2025Article
- Multi-omics identify hallmark protein and lipid features of small extracellular vesicles circulating in human plasma.Nature cell biology · 2025Article
- Mitochondria protect against an intracellular pathogen by restricting access to folate.Science (New York, N.Y.) · 2025Article
- Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.bioRxiv : the preprint server for biology · 2025Article
- Mitochondrial dysfunction in the regulation of aging and aging-related diseases.Cell communication and signaling : CCS · 2025Review
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Authors and funding
26 authors.
Funding
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.
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