Nozaki Yuka, Kobayashi Masaki, Fukuoh Tomoyoshi, Ishimatsu Mamiko, Narita Takumi, Taki Kanari, Hirao Yuto, Ayabe Shota, Yokoyama Miku, Otani Yuina, Mizunoe Yuhei, Matsumoto Mami, Ohno Nobuhiko, Kaifu Tomonori, Okazaki Shogo, Goitsuka Ryo, Nakagawa Yoshimi, Shimano Hitoshi, Iwakura Yoichiro, Higami Yoshikazu
Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.
Sci Rep. 2025 Apr 14;15(1):12839. doi: 10.1038/s41598-025-97307-6.
Most mitochondrial proteins encoded in the nuclear genome are synthesized in the cytoplasm. These proteins subsequently undergo maturation through the cleavage of a signal sequence at the N-terminus by one or two mitochondrial signal peptidases, which is essential for their function within mitochondria. The present study demonstrates that adipocyte-specific knockout of one mitochondrial signal peptidase, mitochondrial intermediate peptidase (MIPEP), resulted in disordered mitochondrial proteostasis of MIPEP substrate proteins and their defective maturation. MIPEP deficiency in white and brown adipocytes suppressed the expression of adipocyte differentiation, lipid metabolism, and mitochondrial biogenesis genes. These alterations led to lipoatrophy in white adipose tissue and the whitening of brown adipose tissue. Additionally, it induced an atypical mitochondrial unfolded protein response and local inflammation in white and brown adipose tissue. Furthermore, it induced fatty liver and splenomegaly and caused systemic impairments in glucose metabolism and inflammation. These findings indicate that maturation defects of certain mitochondrial proteins and subsequent proteostasis disorders in white and brown adipocytes cause chronic and systemic inflammatory and metabolic dysfunctions.
大多数由核基因组编码的线粒体蛋白在细胞质中合成。这些蛋白质随后通过一种或两种线粒体信号肽酶切割N端的信号序列而经历成熟过程，这对它们在线粒体内的功能至关重要。本研究表明，脂肪细胞特异性敲除一种线粒体信号肽酶——线粒体中间肽酶（MIPEP），会导致MIPEP底物蛋白的线粒体蛋白质稳态紊乱及其成熟缺陷。白色和棕色脂肪细胞中MIPEP的缺乏抑制了脂肪细胞分化、脂质代谢和线粒体生物发生基因的表达。这些改变导致白色脂肪组织脂肪萎缩和棕色脂肪组织变白。此外，它还诱导了白色和棕色脂肪组织中不典型的线粒体未折叠蛋白反应和局部炎症。此外，它还诱导了脂肪肝和脾肿大，并导致全身葡萄糖代谢和炎症受损。这些发现表明，白色和棕色脂肪细胞中某些线粒体蛋白的成熟缺陷以及随后的蛋白质稳态紊乱会导致慢性和全身性炎症及代谢功能障碍。
