RT @SableSys: Lovely Promethion-powered science from @briandrew101 & colleagues @MonashUni - imbalanced folate intermediates may be a previ….

RT @EricTopol: Today marks the beginning of OpenRxiv, which replaces bioRxiv and medRxiv, the world's largest preprint platform for life an….

A.

A big thank you to @nhmrc for funding this work as part of the Investigator Grants. Congratulations to the co-first authors of this work Emily King (@EKing_Sci) and Simon Bond.

A major systemic outcome from muscle specific PolG mutation and ISR activation, was the release of the metabolic peptide hormones FGF21 and GDF15, both of which promote weight loss and hypermetabolism. These peptides likely represent a robust biomarker of ISR and disease.

These findings have implications for conditions that are driven by chronic activation of the ISR, and more generally for mitochondrial disease (@AusMito) and PolG disease (@PolGFoundation), where inhibitors of the ISR or therapies that restore folate metabolism, may have efficacy.

This work performed with collaborators from @BakerResearchAu, @MonashSTM and @UniMelb amongst others, proposes that damage to mitochondrial DNA in muscle - elicits changes to folate metabolism, that likely contributes to activation of the integrated stress response (ISR).

Happy to share the final version of our new paper published in @NatureComms describing a novel inducible, tissue specific #PolG mutation mouse model, that provides interesting insights into muscle specific #mitochondria induced stress responses .

Thanks to the @heartfoundation for supporting our labs research @BakerResearchAu led by Simon Bond and collaborators @FebbraioMark . Excited to start this work on cardiac hepatopathy, and trying to understand the mechanisms driving this condition.

RT @MolMetab: RDH11 plays a key role in protecting cells from stress linked to cholesterol synthesis. In vivo studies show RDH11 helps man….

Thanks for the shout out! Appreciate the collaborative support!.

Well done Adelaide!! @BakerResearchAu.

RT @doctorveera: Finally, we now know exactly which region and cell types in the brain are mediating the actions of GLP1R agonists. As ma….

RT @BDI_MDOP: There are only 2 weeks left to submit your abstract for #MDO24 in Lorne, Australia. Submissions for posters and presentations….

Future work in which PolG is disrupted in tissues including neurons, cardiomyocytes, adipocytes and developmental cell types will provide significant opportunities for identification of causal pathways driving mtDNA induced pathologies /10.

Omics data of these mice provides a detailed resource for the study of the mtISR and the nuclear response to mitochondrial stress. These have important implications for #developmental biology, #cellbiology, #metabolism, one-carbon metabolism and #mito disease /9.

These data corroborate previous work showing that plasma levels of GDF15 and FGF21 in humans and mouse models are a useful #biomarker for mtDNA diseases. Our data is one of the first to demonstrate robust increases of these proteins in a model of PolG disease /8.

Our model is the first to allow tissue specific investigations of PolG using the cre-lox system. We show that the rapid weight loss is driven by chronic activation of the integrated stress response (mtISR), leading to persistent upregulation of peptide hormones #FGF21 & #GDF15 /7

PolG mutations a common genetic cause of mitochondrial disease in humans, leading to various pathological outcomes, a major focus of the @PolGFoundation. Thus tissue specific understanding of this aetiology is critical and builds on previous work using mutator and deletor mice /6.

PolG (Polymerase Gamma) is a DNA polymerase found exclusively in the mitochondria, with major roles in replicating and repairing mtDNA. Specific loss of the proofreading domain allow mtDNA replication, but not repair – thus mutations and deletions in mtDNA accrue over time /5.