A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance

Mitochondrial energy metabolism plays an important role in the pathophysiology of insulin resistance. Recently, a missense N437S variant was identified in the MRPP3 gene, which encodes a mitochondrial RNA processing enzyme within the RNase P complex, with predicted impact on metabolism. We used CRISPR-Cas9 genome editing to introduce this variant into the mouse Mrpp3 gene and show that the variant causes insulin resistance on a high-fat diet. The variant did not influence mitochondrial gene expression markedly, but instead, it reduced mitochondrial calcium that lowered insulin release from the pancreatic islet β cells of the Mrpp3 variant mice. Reduced insulin secretion resulted in lower insulin levels that contributed to imbalanced metabolism and liver steatosis in the Mrpp3 variant mice on a high-fat diet. Our findings reveal that the MRPP3 variant may be a predisposing factor to insulin resistance and metabolic disease in the human population

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

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 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 organs that are commonly affected by the 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. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging

Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis

The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the CL biosynthesis gene Crls1 to investigate the effects of CL loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by uncoordinated mitochondrial translation rates and impaired respiratory chain supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of CL resulted in divergent mitochondrial and endoplasmic reticulum stress responses. We show that CL is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 (also known as OXA1L) during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes

Permafrost dynamics structure species compositions of oribatid mite (Acari: Oribatida) communities in sub-Arctic palsa mires

Palsa mires are sub-Arctic peatland complexes, vulnerable ecosystems with patches of permafrost. Permafrost thawing in palsa mires occurs throughout Fennoscandia, probably due to local climatic warming. In palsa mires, permafrost thaw alters hydrological conditions, vegetation structure and microhabitat composition with unknown consequences for invertebrate fauna. This study's objectives were to examine the role of microhabitat heterogeneity and the effects of permafrost dynamics and thaw on oribatid mite communities in palsa mires. Oribatid mites were sampled in two palsa mires in Finland and Norway. Three different types of microhabitats were examined: graminoid-dominated wet sites, herb-dominated small hummocks and evergreen shrub-dominated permafrost-underlain palsa hummocks. The results indicate that permafrost dynamics are an important factor structuring oribatid mite communities in palsa mires. The community composition of oribatid mites differed remarkably among microhabitats. Six species were significantly more abundant in permafrost-underlain microhabitats in relation to non-permafrost microhabitats. None of the species identified occurred exclusively in permafrost-underlain microhabitats. Findings suggest that permafrost thaw may not have an impact on species diversity but may alter community composition of oribatid mites in palsa mire ecosystems