Evidence that mitochondria in macrophages are destroyed by microautophagy
Shiou-Ling Lu, Siyu Chen, Kazuya Noda, Yangjie Li, Chao‐Yuan Tsai, Hiroko Omori, Yumiko Kato, Zi-di Zhang, B. Chen, K. Tokuda, Tongxin Zheng, Masahiro Wakita, Eiji Hara, Mitsunori Fukuda, Yoh Wada, Eiji Morita, Narikazu Uzawa, Shinya Murakami, Takeshi Noda
Abstract
Microautophagy is an intracellular degradation process in which degradatory organelles, such as the lysosome, directly take up substrates by invagination and/or protrusion of their membranes. Here, we provide evidence that Rab32-positive, lysosome-related organelles in macrophages incorporate various other organelles, including endosomes and mitochondria. Our data indicates that, upon exposure to a mitochondria-damaging reagent, mitochondria can be directly engulfed by the lysosome-like organelles independently of macroautophagy or ESCRT machinery. Rab32 GTPase, phosphatidylinositol 3,5-bisphosphates, ubiquitination, and p62/SQSTM1 are crucial for this degradation. Furthermore, the degree of M1 polarization of macrophages, which is facilitated by metabolic reprogramming into increased glycolysis via mitochondrial elimination, is significantly reduced in Rab32/38 double-knockout macrophages. Thus, microautophagy plays a role in the physiological regulation of macrophages. Mitophagy, the selective degradation of mitochondria, has been thought to occur via macroautophagy. Here, the authors present data indicating that microautophagy also mediates mitophagy in macrophages, and that it is essential for immune activation during M1 polarization.