Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University School of Medicine, Seoul, Korea.
Nat Commun. 2022 Mar 14;13(1):1300. doi: 10.1038/s41467-022-28874-9.
Although autophagy is critical for pancreatic β-cell function, the role and mechanism of mitophagy in β-cells are unclear. We studied the role of lysosomal Ca in TFEB activation by mitochondrial or metabolic stress and that of TFEB-mediated mitophagy in β-cell function. Mitochondrial or metabolic stress induced mitophagy through lysosomal Ca release, increased cytosolic Ca and TFEB activation. Lysosomal Ca replenishment by ER- > lysosome Ca refilling was essential for mitophagy. β-cell-specific Tfeb knockout (Tfeb) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O consumption. Tfeb mice showed aggravation of HFD-induced glucose intolerance and impaired insulin release. Metabolic or mitochondrial stress induced TFEB-dependent expression of mitophagy receptors including Ndp52 and Optn, contributing to the increased mitophagy. These results suggest crucial roles of lysosomal Ca release coupled with ER- > lysosome Ca refilling and TFEB activation in mitophagy and maintenance of pancreatic β-cell function during metabolic stress.
尽管自噬对于胰腺β细胞的功能至关重要，但线粒体自噬在β细胞中的作用和机制尚不清楚。我们研究了溶酶体钙在由线粒体或代谢应激引起的 TFEB 激活中的作用，以及 TFEB 介导的线粒体自噬在β细胞功能中的作用。线粒体或代谢应激通过溶酶体钙释放、增加细胞浆钙和 TFEB 激活诱导线粒体自噬。内质网-溶酶体钙再填充是线粒体自噬所必需的。β细胞特异性 Tfeb 敲除（Tfeb）消除了高脂肪饮食（HFD）诱导的线粒体自噬，伴随着 ROS 增加和线粒体细胞色素 c 氧化酶活性或 O 消耗减少。Tfeb 小鼠表现出 HFD 诱导的葡萄糖不耐受加重和胰岛素释放受损。代谢或线粒体应激诱导 TFEB 依赖性表达包括 Ndp52 和 Optn 在内的线粒体自噬受体，有助于增加线粒体自噬。这些结果表明，在代谢应激期间，溶酶体钙释放与内质网-溶酶体钙再填充和 TFEB 激活耦联对于线粒体自噬和维持胰腺β细胞功能至关重要。
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