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Journal Article

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


Milenkovic,  D.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Rossetti, G., Ermer, J. A., Stentenbach, M., Siira, S. J., Richman, T. R., Milenkovic, D., et al. (2021). A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance. Sci Adv, 7(39), eabi7514. doi:10.1126/sciadv.abi7514.

Cite as: https://hdl.handle.net/21.11116/0000-000B-2B7E-9
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.