Dataset Information

Comprehensive respiratory phenomics across multiple models of mitochondrial protein hyperacylation reveals a paradoxically marginal impact on bioenergetics

ABSTRACT: Acyl CoA metabolites derived from catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translation modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong correlative connection between mitochondrial hyperacylation and disease; however, the functional consequences of these modifications remain uncertain. Here, we used a comprehensive respiratory diagnostics platform to evaluate three disparate mouse models of mitochondrial hyperacylation in heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), the SIRT5 demalonylase/desuccinylase, or the SIRT3 deacetylase. In each case, elevated acylation was accompanied by surprisingly marginal respiratory phenotypes. Of the >30 mitochondrial energy fluxes evaluated, the only outcome observed consistently across models was ~15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that have minimal impact on mitochondrial bioenergetics. See Fisher-Wellman et. al. 2018 for further experimental details, reagents, and references.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Deborah M. Muoio

PROVIDER: PXD011375 | JPOST Repository | Thu Feb 07 00:00:00 GMT 2019

REPOSITORIES: jPOST

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Publications

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Fisher-Wellman Kelsey H KH Draper James A JA Davidson Michael T MT Williams Ashley S AS Narowski Tara M TM Slentz Dorothy H DH Ilkayeva Olga R OR Stevens Robert D RD Wagner Gregory R GR Najjar Rami R Hirschey Mathew D MD Thompson J Will JW Olson David P DP Kelly Daniel P DP Koves Timothy R TR Grimsrud Paul A PA Muoio Deborah M DM

Cell reports 20190201 6

Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respi ...[more]

PMID: 30726738

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Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1? and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration. To evaluate the effect of TG2 inhibition (treatment with ZDON, Boc-DON, CystamineA, and Control) in striatal cell lines from a transgenic model of Huntington disease (Q111) vs. control (Q7). One sample (WT.boc.3, 4068264015_G) failed the QC test and was excluded from further analyses.

Dataset Information

Comprehensive respiratory phenomics across multiple models of mitochondrial protein hyperacylation reveals a paradoxically marginal impact on bioenergetics

Publications

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Similar Datasets

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