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.

中文翻译：

---

线粒体 RNA 加工酶的一种常见遗传变异易导致胰岛素抵抗

线粒体能量代谢在胰岛素抵抗的病理生理学中起重要作用。最近，在MRPP3基因中发现了一个错义 N437S 变体，该基因编码 RNase P 复合物中的一种线粒体 RNA 加工酶，预计对代谢有影响。我们使用 CRISPR-Cas9 基因组编辑将该变体引入小鼠Mrpp3基因，并表明该变体在高脂肪饮食中导致胰岛素抵抗。该变体没有显着影响线粒体基因表达，而是降低了线粒体钙，从而降低了Mrpp3胰岛 β 细胞的胰岛素释放变异小鼠。胰岛素分泌减少导致胰岛素水平降低，从而导致高脂肪饮食的Mrpp3变异小鼠的代谢失衡和肝脏脂肪变性。我们的研究结果表明，MRPP3 变体可能是人群中胰岛素抵抗和代谢疾病的诱发因素。