Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions
Abstract 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...
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Nature Portfolio
2025-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-97307-6 |
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| author | Yuka Nozaki Masaki Kobayashi Tomoyoshi Fukuoh Mamiko Ishimatsu Takumi Narita Kanari Taki Yuto Hirao Shota Ayabe Miku Yokoyama Yuina Otani Yuhei Mizunoe Mami Matsumoto Nobuhiko Ohno Tomonori Kaifu Shogo Okazaki Ryo Goitsuka Yoshimi Nakagawa Hitoshi Shimano Yoichiro Iwakura Yoshikazu Higami |
| author_facet | Yuka Nozaki Masaki Kobayashi Tomoyoshi Fukuoh Mamiko Ishimatsu Takumi Narita Kanari Taki Yuto Hirao Shota Ayabe Miku Yokoyama Yuina Otani Yuhei Mizunoe Mami Matsumoto Nobuhiko Ohno Tomonori Kaifu Shogo Okazaki Ryo Goitsuka Yoshimi Nakagawa Hitoshi Shimano Yoichiro Iwakura Yoshikazu Higami |
| author_sort | Yuka Nozaki |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-07ca8f617fce4cddace436454056357d |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-07ca8f617fce4cddace436454056357d2025-08-20T02:17:50ZengNature PortfolioScientific Reports2045-23222025-04-0115111910.1038/s41598-025-97307-6Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctionsYuka Nozaki0Masaki Kobayashi1Tomoyoshi Fukuoh2Mamiko Ishimatsu3Takumi Narita4Kanari Taki5Yuto Hirao6Shota Ayabe7Miku Yokoyama8Yuina Otani9Yuhei Mizunoe10Mami Matsumoto11Nobuhiko Ohno12Tomonori Kaifu13Shogo Okazaki14Ryo Goitsuka15Yoshimi Nakagawa16Hitoshi Shimano17Yoichiro Iwakura18Yoshikazu Higami19Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceSection of Electron Microscopy, Supportive Center for Brain Research, National Institute for Physiological SciencesDepartment of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical UniversityDivision of Immunology, Faculty of Medicine, Tohoku Medical and Pharmaceutical UniversityResearch Institute for Biomedical Sciences (RIBS), Tokyo University of ScienceResearch Institute for Biomedical Sciences (RIBS), Tokyo University of ScienceDivision of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of ToyamaDepartment of Endocrinology and Metabolism, Institute of Medicine, University of TsukubaResearch Institute for Biomedical Sciences (RIBS), Tokyo University of ScienceLaboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceAbstract 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.https://doi.org/10.1038/s41598-025-97307-6 |
| spellingShingle | Yuka Nozaki Masaki Kobayashi Tomoyoshi Fukuoh Mamiko Ishimatsu Takumi Narita Kanari Taki Yuto Hirao Shota Ayabe Miku Yokoyama Yuina Otani Yuhei Mizunoe Mami Matsumoto Nobuhiko Ohno Tomonori Kaifu Shogo Okazaki Ryo Goitsuka Yoshimi Nakagawa Hitoshi Shimano Yoichiro Iwakura Yoshikazu Higami Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions Scientific Reports |
| title | Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions |
| title_full | Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions |
| title_fullStr | Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions |
| title_full_unstemmed | Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions |
| title_short | Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions |
| title_sort | mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions |
| url | https://doi.org/10.1038/s41598-025-97307-6 |
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