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<p>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&#xa0;of the mtISR remain mostly unknown. A gene often associated with mtDNA mutations/deletions is <i>Polg1</i>, 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月8日

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  • 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

摘要

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.