Department of Anesthesiology, Kindai University Faculty of Medicine, Osaka, Japan.
Kindai University Life Science Research Institute, Kindai University, Osaka, Japan.
Sci Rep. 2020 Feb 28;10(1):3735. doi: 10.1038/s41598-020-60346-2.
Elevation of the levels of reactive oxygen species (ROS) is a major tissue-degenerative phenomenon involved in aging and aging-related diseases. The detailed mechanisms underlying aging-related ROS generation remain unclear. Presently, the expression of microRNA (miR)-142-5p was significantly upregulated in bone marrow mesenchymal stem cells (BMMSCs) of aged mice. Overexpression of miR-142 and subsequent observation revealed that miR-142 involved ROS accumulation through the disruption of selective autophagy for peroxisomes (pexophagy). Mechanistically, attenuation of acetyltransferase Ep300 triggered the upregulation of miR-142 in aged BMMSCs, and miR-142 targeted endothelial PAS domain protein 1 (Epas1) was identified as a regulatory protein of pexophagy. These findings support a novel molecular mechanism relating aging-associated ROS generation and organelle degradation in BMMSCs, and suggest a potential therapeutic target for aging-associated disorders that are accompanied by stem cell degeneration.
活性氧（ROS）水平的升高是衰老和与衰老相关疾病中涉及的主要组织退化现象。与衰老相关的 ROS 产生的详细机制仍不清楚。目前，衰老小鼠骨髓间充质干细胞（BMMSC）中 microRNA（miR）-142-5p 的表达明显上调。miR-142 的过表达和随后的观察表明，miR-142 通过破坏过氧化物酶体的选择性自噬（pexophagy）导致 ROS 积累。在机制上，乙酰转移酶 Ep300 的衰减触发了衰老 BMMSC 中 miR-142 的上调，并且鉴定出内皮 PAS 结构域蛋白 1（Epas1）作为 pexophagy 的调节蛋白。这些发现支持了一个新的分子机制，涉及到 BMMSC 中与衰老相关的 ROS 产生和细胞器降解，并且为伴有干细胞退化的与衰老相关的疾病提供了一个潜在的治疗靶点。
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