Metabolic syndrome is a growing concern in developed societies and due to its polygenic nature, the genetic component is only slowly being elucidated. Common mitochondrial DNA sequence variants have been associated with symptoms of metabolic syndrome and may, therefore, be relevant players in the genetics of metabolic syndrome. We investigate the effect of mitochondrial sequence variation on the metabolic phenotype in conplastic rat strains with identical nuclear but unique mitochondrial genomes, challenged by high-fat diet. We find that the variation in mitochondrial rRNA sequence represents risk factor in the insulin resistance development, which is associated with diacylglycerols accumulation, induced by tissue-specific reduction of the oxidative capacity. These metabolic perturbations stem from the 12S rRNA sequence variation affecting mitochondrial ribosome assembly and translation. Our work demonstrates that physiological variation in mitochondrial rRNA might represent a relevant underlying factor in the progression of metabolic syndrome.

Institute of Parasitology Biology Centre Czech Academy of Sciences České Budějovice Czech Republic

Laboratory of Bioenergetics Institute of Physiology Czech Academy of Sciences Prague Czech Republic

Laboratory of Developmental Cardiology Institute of Physiology Czech Academy of Sciences Prague Czech Republic

Laboratory of Genetics of Model Diseases Institute of Physiology Czech Academy of Sciences Prague Czech Republic

Laboratory of Translational Metabolism Institute of Physiology Czech Academy of Sciences Prague Czech Republic

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Zobrazit více v PubMed

Kenney, M. C. et al. Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: implications for population susceptibility to diseases. PubMed DOI PMC

Rath, S. et al. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations. PubMed DOI PMC

Cagin, U. & Enriquez, J. A. The complex crosstalk between mitochondria and the nucleus: What goes in between? PubMed DOI

Dennerlein, S., Wang, C. & Rehling, P. Plasticity of Mitochondrial Translation. PubMed DOI

Estopinal, C. B. et al. Mitochondrial haplogroups are associated with severity of diabetic retinopathy. PubMed DOI PMC

Chinnery, P. F., Elliott, H. R., Syed, A., Rothwell, P. M. & Oxford Vascular, S. Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic association study. PubMed DOI PMC

Martikainen, M. H., Ronnemaa, T. & Majamaa, K. Association of mitochondrial DNA haplogroups and vascular complications of diabetes mellitus: a population-based study. PubMed DOI

Bellizzi, D. et al. Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines. PubMed DOI

Grundy, S. M. Obesity, metabolic syndrome, and cardiovascular disease. PubMed DOI

Castro, A. V., Kolka, C. M., Kim, S. P. & Bergman, R. N. Obesity, insulin resistance and comorbidities? Mechanisms of association. PubMed DOI PMC

Vazquez, G., Duval, S., Jacobs, D. R. Jr. & Silventoinen, K. Comparison of body mass index, waist circumference, and waist/hip ratio in predicting incident diabetes: a meta-analysis. PubMed DOI

Unger, R. H. Lipotoxic diseases. PubMed DOI

Boutari, C. & Mantzoros, C. S. A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. PubMed DOI PMC

Kelley, D. E., Goodpaster, B., Wing, R. R. & Simoneau, J. A. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. PubMed

Mootha, V. K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. PubMed DOI

Chavez, J. A. & Summers, S. A. A ceramide-centric view of insulin resistance. PubMed DOI

Yu, C. et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. PubMed DOI

Teruel, T., Hernandez, R. & Lorenzo, M. Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. PubMed DOI

Powell, D. J., Hajduch, E., Kular, G. & Hundal, H. S. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. PubMed DOI PMC

Anderson, E. J. et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. PubMed DOI PMC

Jani, S. et al. Distinct mechanisms involving diacylglycerol, ceramides, and inflammation underlie insulin resistance in oxidative and glycolytic muscles from high fat-fed rats. PubMed DOI PMC

Pickup, J. C. & Crook, M. A. Is type II diabetes mellitus a disease of the innate immune system? PubMed DOI

Wu, H. & Ballantyne, C. M. Metabolic inflammation and insulin resistance in obesity. PubMed DOI PMC

Tornatore, L., Thotakura, A. K., Bennett, J., Moretti, M. & Franzoso, G. The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. PubMed DOI

Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. PubMed DOI PMC

Samuel, V. T. & Shulman, G. I. Mechanisms for insulin resistance: common threads and missing links. PubMed DOI PMC

Houstek, J. et al. Effects of mtDNA in SHR-mtF344 versus SHR conplastic strains on reduced OXPHOS enzyme levels, insulin resistance, cardiac hypertrophy, and systolic dysfunction. PubMed DOI

Pravenec, M.

Pravenec, M. et al. Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains. PubMed DOI PMC

Pravenec, M. et al. Conplastic strains for identification of retrograde effects of mitochondrial dna variation on cardiometabolic traits in the spontaneously hypertensive rat. PubMed DOI PMC

Houstek, J. et al. Nonsynonymous variants in mt-Nd2, mt-Nd4, and mt-Nd5 are linked to effects on oxidative phosphorylation and insulin sensitivity in rat conplastic strains. PubMed DOI PMC

Korshunov, S. S., Skulachev, V. P. & Starkov, A. A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. PubMed DOI

Lambert, A. J. & Brand, M. D. Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. PubMed DOI PMC

Cai, N. et al. Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases. PubMed DOI

Itoh, Y. et al. Mechanism of mitoribosomal small subunit biogenesis and preinitiation. PubMed DOI PMC

Vila-Sanjurjo, A., Mallo, N., Atkins, J. F., Elson, J. L. & Smith, P. M. Our current understanding of the toxicity of altered mito-ribosomal fidelity during mitochondrial protein synthesis: What can it tell us about human disease? PubMed DOI PMC

Harper, N. J., Burnside, C. & Klinge, S. Principles of mitoribosomal small subunit assembly in eukaryotes. PubMed DOI PMC

Nuskova, H. et al. Biochemical thresholds for pathological presentation of ATP synthase deficiencies. PubMed DOI

Rossignol, R. et al. Mitochondrial threshold effects. PubMed DOI PMC

Rossignol, R., Malgat, M., Mazat, J. P. & Letellier, T. Threshold effect and tissue specificity. Implication for mitochondrial cytopathies. PubMed DOI

McLaughlin, T., Ackerman, S. E., Shen, L. & Engleman, E. Role of innate and adaptive immunity in obesity-associated metabolic disease. PubMed DOI PMC

Ludwig-Slomczynska, A. H. & Rehm, M. Mitochondrial genome variations, mitochondrial-nuclear compatibility, and their association with metabolic diseases. PubMed DOI

Fang, H. et al. mtDNA Haplogroup N9a Increases the Risk of Type 2 Diabetes by Altering Mitochondrial Function and Intracellular Mitochondrial Signals. PubMed DOI

Chalkia, D. et al. Mitochondrial DNA associations with East Asian metabolic syndrome. PubMed DOI PMC

Latorre-Pellicer, A. et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. PubMed DOI

Goios, A., Pereira, L., Bogue, M., Macaulay, V. & Amorim, A. mtDNA phylogeny and evolution of laboratory mouse strains. PubMed DOI PMC

Kleinert, M. et al. Animal models of obesity and diabetes mellitus. PubMed DOI

Dunham-Snary, K. J. et al. Mitochondrial - nuclear genetic interaction modulates whole body metabolism, adiposity and gene expression in vivo. PubMed DOI PMC

Kunstner, A., Schilf, P., Busch, H., Ibrahim, S. M. & Hirose, M. Changes of gut microbiota by natural mtDNA variant differences augment susceptibility to metabolic disease and ageing. PubMed DOI PMC

Qatanani, M. & Lazar, M. A. Mechanisms of obesity-associated insulin resistance: many choices on the menu. PubMed DOI

Sergi, D. et al. Mitochondrial (Dys)function and insulin resistance: from pathophysiological molecular mechanisms to the impact of diet. PubMed DOI PMC

Kim, J. Y., Hickner, R. C., Cortright, R. L., Dohm, G. L. & Houmard, J. A. Lipid oxidation is reduced in obese human skeletal muscle. PubMed DOI

Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. PubMed DOI

Cardoso, A. R., Kakimoto, P. A. & Kowaltowski, A. J. Diet-sensitive sources of reactive oxygen species in liver mitochondria: role of very long chain acyl-CoA dehydrogenases. PubMed DOI PMC

Raffaella, C. et al. Alterations in hepatic mitochondrial compartment in a model of obesity and insulin resistance. PubMed DOI

Cole, M. A. et al. A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. PubMed DOI PMC

Shao, D. et al. Increasing fatty acid oxidation prevents high-fat diet-induced cardiomyopathy through regulating Parkin-mediated mitophagy. PubMed DOI PMC

Murashige, D. et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. PubMed DOI PMC

Arguello, T., Kohrer, C., RajBhandary, U. L. & Moraes, C. T. Mitochondrial methionyl N-formylation affects steady-state levels of oxidative phosphorylation complexes and their organization into supercomplexes. PubMed DOI PMC

Tucker, E. J. et al. Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. PubMed DOI PMC

Aibara, S., Singh, V., Modelska, A. & Amunts, A. Structural basis of mitochondrial translation. PubMed DOI PMC

Vila-Sanjurjo, A. et al. Structural analysis of mitochondrial rRNA gene variants identified in patients with deafness. PubMed DOI PMC

Amunts, A., Brown, A., Toots, J., Scheres, S. H. W. & Ramakrishnan, V. Ribosome. The structure of the human mitochondrial ribosome. PubMed DOI PMC

Bolze, A. et al. A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans. DOI

None

Guan, M. X., Fischel-Ghodsian, N. & Attardi, G. Nuclear background determines biochemical phenotype in the deafness-associated mitochondrial 12S rRNA mutation. PubMed DOI

Lee, S. et al. Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status or hearing. PubMed DOI PMC

O’Sullivan, M. et al. Mitochondrial m.1584A 12S m62A rRNA methylation in families with m.1555A>G associated hearing loss. PubMed DOI PMC

Raimundo, N. et al. Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. PubMed DOI PMC

Aboulmaouahib, B. et al. First mitochondrial genome-wide association study with metabolomics. PubMed DOI PMC

Kong, B. S., Lee, C. & Cho, Y. M. Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases. PubMed DOI PMC

Vila-Sanjurjo, A., Smith, P. M. & Elson, J. L. Heterologous Inferential Analysis (HIA) and Other Emerging Concepts: In Understanding Mitochondrial Variation In Pathogenesis: There is no More Low-Hanging Fruit. PubMed DOI

Aw, W. C. et al. Genotype to phenotype: Diet-by-mitochondrial DNA haplotype interactions drive metabolic flexibility and organismal fitness. PubMed DOI PMC

Dobson, A. J. et al. Mitonuclear interactions shape both direct and parental effects of diet on fitness and involve a SNP in mitoribosomal 16s rRNA. PubMed DOI PMC

Haumann, S. et al. Mitochondrial DNA mutations induce mitochondrial biogenesis and increase the tumorigenic potential of Hodgkin and Reed-Sternberg cells. PubMed DOI

Akbergenov, R. et al. Mutant MRPS5 affects mitoribosomal accuracy and confers stress-related behavioral alterations. PubMed DOI PMC

Shcherbakov, D. et al. Mitochondrial mistranslation in brain provokes a metabolic response which mitigates the age-associated decline in mitochondrial gene expression. PubMed DOI PMC

Shcherbakov, D. Sr. et al. Mitochondrial misreading in skeletal muscle accelerates metabolic aging and confers lipid accumulation and increased inflammation. PubMed DOI PMC

Ferreira, N. et al. Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation. PubMed DOI PMC

Richman, T. R. et al. Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan. PubMed DOI PMC

Antunes, L. C., Elkfury, J. L., Jornada, M. N., Foletto, K. C. & Bertoluci, M. C. Validation of HOMA-IR in a model of insulin-resistance induced by a high-fat diet in Wistar rats. PubMed DOI

Pecinova, A., Drahota, Z., Nuskova, H., Pecina, P. & Houstek, J. Evaluation of basic mitochondrial functions using rat tissue homogenates. PubMed DOI

Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. PubMed DOI

Seluanov, A., Vaidya, A. & Gorbunova, V. Establishing primary adult fibroblast cultures from rodents. PubMed DOI PMC

Pecinova, A. et al. Pleiotropic effects of biguanides on mitochondrial reactive oxygen species production. PubMed DOI PMC

Miwa, S. et al. Carboxylesterase converts Amplex red to resorufin: Implications for mitochondrial H PubMed DOI PMC

Hricko, J. et al. Short-term stability of serum and liver extracts for untargeted metabolomics and lipidomics. PubMed DOI PMC

Sistilli, G. et al. Krill oil supplementation reduces exacerbated hepatic steatosis induced by thermoneutral housing in mice with diet-induced obesity. PubMed DOI PMC

Cajka, T. et al. Optimization of mobile phase modifiers for Fast LC-MS-based untargeted metabolomics and lipidomics. PubMed DOI PMC

Tsugawa, H. et al. A lipidome atlas in MS-DIAL 4. PubMed DOI

Pang, Z. et al. Using MetaboAnalyst 5.0 for LC-HRMS spectra processing, multi-omics integration and covariate adjustment of global metabolomics data. PubMed DOI

Markovic, A. et al. Genetic complementation of ATP synthase deficiency due to dysfunction of TMEM70 assembly factor in rat. PubMed DOI PMC

Johnston, H. E. et al. Solvent precipitation SP3 (SP4) enhances recovery for proteomics sample preparation without magnetic beads. PubMed DOI PMC

Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. PubMed DOI PMC

Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. PubMed DOI PMC

Sadakierska-Chudy, A. et al. The alterations in mitochondrial DNA copy number and nuclear-encoded mitochondrial genes in rat brain structures after cocaine self-administration. PubMed DOI PMC

Mracek, T., Pecinova, A., Vrbacky, M., Drahota, Z. & Houstek, J. High efficiency of ROS production by glycerophosphate dehydrogenase in mammalian mitochondria. PubMed DOI

Pajuelo Reguera, D. et al. Cytochrome c oxidase subunit 4 isoform exchange results in modulation of oxygen affinity. PubMed DOI PMC

Pravenec, M. et al. Mutant Wars2 gene in spontaneously hypertensive rats impairs brown adipose tissue function and predisposes to visceral obesity. PubMed DOI

Cunatova, K. et al. Loss of COX4I1 Leads to combined respiratory chain deficiency and impaired mitochondrial protein synthesis. PubMed DOI PMC

Schagger, H. & von Jagow, G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. PubMed DOI

Sievers, F. et al. Fast, scalable generation of high-quality protein multiple sequence alignments using clustal omega. PubMed DOI PMC

Kummer, E., Schubert, K. N., Schoenhut, T., Scaiola, A. & Ban, N. Structural basis of translation termination, rescue, and recycling in mammalian mitochondria. PubMed DOI

Goddard, T. D. et al. UCSF ChimeraX: Meeting modern challenges in visualization and analysis. PubMed DOI PMC

Mettl15-Mettl17 modulates the transition from early to late pre-mitoribosome