Dataset Information

Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced life-span

ABSTRACT: Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation using mutant mice with error-prone (Mrps12ep/ep) or hyper-accurate (Mrps12ha/ha) mitochondrial ribosomes and their effects on lifespan. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organ types that are commonly affected by metabolic disease, the heart and the liver, Mrps12ep/ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha/ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. While these findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues, they also suggest that trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes toward commonly encountered stressful environmental conditions or aging.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Mark Larance

LAB HEAD: Mark Larance

PROVIDER: PXD024633 | Pride | 2021-09-10

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20200327_Eclipse_ML_AF_EXP1_Heart_EP_701.raw	Raw
	20200327_Eclipse_ML_AF_EXP1_Heart_EP_702.raw	Raw
	20200327_Eclipse_ML_AF_EXP1_Heart_EP_707.raw	Raw
	20200327_Eclipse_ML_AF_EXP1_Heart_EP_724.raw	Raw
	20200327_Eclipse_ML_AF_EXP1_Heart_EP_769.raw	Raw

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Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.

Richman Tara R TR Ermer Judith A JA Siira Stefan J SJ Kuznetsova Irina I Brosnan Christopher A CA Rossetti Giulia G Baker Jessica J Perks Kara L KL Cserne Szappanos Henrietta H Viola Helena M HM Gray Nicola N Larance Mark M Hool Livia C LC Zuryn Steven S Rackham Oliver O Filipovska Aleksandra A

Aging cell 20210607 7

Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12ep/ep ) or hyper-accurate (Mrps12ha/ha ) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in ...[more]

PMID: 34096683

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Project description:How signals from fatty acid metabolism are translated into changes in food intake remains unclear. Previously we reported that mice with a genetic inactivation of Acads (short-chain acyl-CoA dehydrogenase), encoding the enzyme responsible for mitochondrial beta-oxidation of C4-C6 short-chain fatty acids (SCFAs), shift consumption away from fat and toward carbohydrate when offered a choice. This finding demonstrated that the loss of a specific enzyme in fatty acid oxidation alters the choice of diet intake. To our knowledge, there are no reports of studies on the effects of dietary fat on the brain transcriptome in genetic models of fatty acid oxidation deficiency. The current study aimed to identify molecular mediators underlying the effects of SCFA oxidation deficiency on food intake. The current study aimed to identify molecular mediators underlying the effects of SCFA oxidation deficiency on food intake. We performed a transcriptional screen for gene expression in brain tissue of Acads-/- and Acads+/+ mice fed either high-fat (HF) or low-fat (LF) diet for 2 d. Ingenuity Pathway Analysis revealed three top-scoring pathways significantly modified by genotype or diet: oxidative phosphorylation, mitochondrial dysfunction, and CREB signaling in neurons. A comparison of statistically significant responses in HF Acads-/- vs. HF Acads+/+ (3917) and Acads+/+ HF vs. LF Acads+/+ (3879) revealed 2551 genes or approximately 65% in common between the two experimental comparisons. All but one of these genes were expressed in opposite direction with similar magnitude, demonstrating that Acads-deficient mice fed HF diet display transcriptional responses that mimic those of wildtype Acads+/+ mice fed LF diet. Intriguingly, genes involved in energy sensing and metabolism followed this pattern. Quantitative RT-PCR in hypothalamus confirmed the dysregulation of several genes in these pathways. Western blotting showed that the combination of Acads deficiency and HF diet increased hypothalamic AMP-kinase, a key protein in an energy-sensing cascade that responds to depletion of ATP. Our results suggest that the decreased beta oxidation of short-chain fatty acids in Acads-deficient mice fed HF diet produces a state of energy deficiency in the brain and that AMP-kinase is the cellular energy-sensing mechanism linking fatty acid oxidation to feeding behavior in this model. Twelve-week old male BALB/cByJ (Acads-/-) and BALB/cByKZ (Acads+/+) mice were fed a high-fat (D12331; Research Diets) and low-fat (D12329) diet for two days. Total RNA from whole brain tissue was obtained from three mutant (Acads-/-) and three wild-type (Acads+/+) mice of each diet group. All mice had similar body weights before diets were initiated. Gene expression in brain was compared between strains and between diets. Twelve-week old male BALB/cByJ (Acads-/-) and BALB/cByKZ (Acads+/+) mice were fed a high-fat (D12331; Research Diets) and low-fat (D12329) diet for two days. Total RNA from liver was obtained from three mutant (Acads-/-) and three wild-type (Acads+/+) mice of each diet group. All mice had similar body weights before diets were initiated. Gene expression in liver was compared between strains and diets.