Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions
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.
Authors
- Yuka Nozaki (ORCID: https://orcid.org/0009-0002-4656-3274)
- Masaki Kobayashi (ORCID: https://orcid.org/0000-0002-0985-0322)
- Ryo Goitsuka (ORCID: https://orcid.org/0000-0002-1137-9760)
- Shogo Okazaki (ORCID: https://orcid.org/0009-0008-2243-5140)
- Hitoshi Shimano (ORCID: https://orcid.org/0000-0002-5562-5572)
- Takumi Narita (ORCID: https://orcid.org/0000-0002-8939-4346)
- Kanari Taki
- Yoshikazu Higami (ORCID: https://orcid.org/0000-0003-1381-0777)
- M. Yokoyama
- Yuto Hirao
- Yuhei Mizunoe (ORCID: https://orcid.org/0000-0001-6716-1544)
- Mami Matsumoto (ORCID: https://orcid.org/0000-0003-1406-5916)
- Yoichiro Iwakura (ORCID: https://orcid.org/0000-0002-9934-5775)
- Yoshimi Nakagawa (ORCID: https://orcid.org/0000-0001-8710-5232)
- Nobuhiko Ohno (ORCID: https://orcid.org/0000-0002-6536-2753)
- Tomonori Kaifu (ORCID: https://orcid.org/0000-0002-2614-1472)
- Tomoyoshi Fukuoh (ORCID: https://orcid.org/0009-0009-6524-523X)
- Yuina Otani
- Mamiko Ishimatsu
- Shota Ayabe
Institutions
- University of Tsukuba (JP)
- Jichi Medical University (JP)
- Tokyo University of Science (JP)
- Ochanomizu University (JP)
- Nagoya City University (JP)
- National Institute for Physiological Sciences (JP)
- University of Toyama (JP)
- The University of Tokyo (JP)
- Tohoku Medical and Pharmaceutical University (JP)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1038/s41598-025-97307-6
- Citations
- 2
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- Uehara Memorial Foundation
- Jichi Medical University
- Mishima Kaiun Memorial Foundation
- Japan Society for the Promotion of Science
- National Institute for Physiological Sciences