Comparative multi-omic analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.

TitleComparative multi-omic analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.
Publication TypeJournal Article
Year of Publication2023
AuthorsSayles NM, Napierala JS, Anrather J, Diedhiou N, Li J, Napierala M, Puccio H, Manfredi G
JournalDis Model Mech
Date Published2023 Oct 01
KeywordsAnimals, Cardiomyopathies, Friedreich Ataxia, Heart, Iron-Binding Proteins, Mice, Mice, Knockout, Multiomics

Cardiomyopathy is often fatal in Friedreich ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, the ISRmt has not been investigated in models with disease-relevant, partial decrease in FXN. We characterized the heart transcriptomes and metabolomes of three mouse models with varying degrees of FXN depletion: YG8-800, KIKO-700 and FXNG127V. Few metabolites were changed in YG8-800 mice, which did not provide a signature of cardiomyopathy or ISRmt; several metabolites were altered in FXNG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FXNG127V hearts. However, these changes were surprisingly mild even at advanced age (18 months), despite a severe decrease in FXN levels to 1% of those of wild type. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

Alternate JournalDis Model Mech
PubMed ID37691621
PubMed Central IDPMC10581388
Grant ListR35 NS122209 / NS / NINDS NIH HHS / United States
R01NS121038 / NS / NINDS NIH HHS / United States
F31HL154651 / HL / NHLBI NIH HHS / United States