Kidney-Related Function of Mitochondrial Protein Mitoregulin

Abstract

A small protein, Mitoregulin (Mtln), localizes in mitochondria and contributes to oxidative phosphorylation and fatty acid metabolism. Mtln knockout mice develop obesity on a high-fat diet, demonstrating elevated cardiolipin damage and suboptimal creatine kinase oligomerization in muscle tissue. Kidneys heavily depend on the oxidative phosphorylation in mitochondria. Here we report kidney-related phenotypes in aged Mtln knockout mice. Similar to Mtln knockout mice muscle mitochondria, those of the kidney demonstrate a decreased respiratory complex I activity and excessive cardiolipin damage. Aged male mice carrying Mtln knockout demonstrated an increased frequency of renal proximal tubules’ degeneration. At the same time, a decreased glomerular filtration rate has been more frequently detected in aged female mice devoid of Mtln. An amount of Mtln partner protein, Cyb5r3, is drastically decreased in the kidneys of Mtln knockout mice.

Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury

“…Weakened mitochondrial membranes in Mtln-KO mice might arise from loss of a direct Mtlnstabilizing effect or may develop after accumulation of lipid damage and remodeling that occurs over time. In fact, a recent report shows onset of kidney dysfunction and pathology in aged (~2 years-old) but not young Mtln-KO mice, and those authors propose dysfunction develops after chronic CL oxidation and remodeling 17 . To determine whether our phenotype could develop in a shorter timeframe, we used the CRISPR-Cas9 system to establish acute Mtln-KO in young mice.…”

“…In line with this, loss of Mtln impacts mitochondrial respiration and ROS production 1,[8][9][10][11] . In addition, several studies support that Mtln affects various other pathways and phenotypes, including lipid metabolism 2,8,[12][13][14] , mitochondrial-ER contacts and ER stress signaling 10 , cancer cell migration/invasion 15 , skeletal muscle performance 2,9,13 , myocyte differentiation or regeneration 9,16 , and normal 17 and diseased kidney 18 phenotypes.…”

Molecular Mechanisms Associated with Aging Kidneys and Future Perspectives

“…The deletion of mitoregulin (Mtln), located in mitochondria and contributing to oxidative phosphorylation and fatty acid metabolism, might accelerate aging. Old Mtln KO mice exhibited an increased frequency of renal proximal tubule degeneration and a reduced glomerular filtration rate compared with wild-type mice [83]. Phosphatase and tensin homolog-induced kinase 1 (PINK1) is known to regulate mitochondrial function.…”