Physiological variability in mitochondrial rRNA may predispose to metabolic syndrome

ABSTRACT: Objectives: Metabolic syndrome and its associated comorbidities are a growing concern in developed societies. Due to its polygenic nature, the genetic component of metabolic syndrome is only slowly being elucidated. Common mitochondrial DNA sequence variants have been associated with late-onset human diseases, including cardiovascular disease or type 2 diabetes mellitus, and may therefore be relevant players in the genetics of metabolic syndrome. Methods: In the present study, we investigate the effect of mitochondrial sequence variation on the metabolic phenotype in conplastic rat strains with identical nuclear but unique mitochondrial genomes that differ in the sequence of oxidative phosphorylation structural proteins, tRNAs and rRNAs. Results: Exposure to the high-fat diet led to the development of insulin resistance in the conplastic animals, which was associated with the reduced oxidative capacity of the heart (but not the liver) mitochondria. Reduced fatty acid oxidation led to the accumulation of bioactive diacylglycerols and subsequent inhibition of insulin signaling. Conclusions: We propose that these metabolic perturbations stem from the 12S rRNA sequence variation, which affects mitoribosome assembly and thus mitochondrial translation. Our work has demonstrated that physiological sequence variation in mitochondrial rRNA may be a relevant underlying factor in the progression of metabolic syndrome.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart, Liver

SUBMITTER: Marek Vrbacky  

LAB HEAD: Tomas Mracek

PROVIDER: PXD045910 | Pride | 2024-08-13

REPOSITORIES: Pride