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  3. Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis

Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis

  • Cell Metab. 2023 Feb 7;35(2):345-360.e7. doi: 10.1016/j.cmet.2023.01.003.
Joonho Suh 1,  Na-Kyung Kim 1,  Wonn Shim 1,  Seung-Hoon Lee 2,  Hyo-Jeong Kim 3,  Eunyoung Moon 4,  Hiromi Sesaki 5,  Jae Hyuck Jang 6,  Jung-Eun Kim 2,  Yun-Sil Lee 7
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.
  • 2 Department of Molecular Medicine, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
  • 3 Electron Microscopy Research Center, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.
  • 4 Electron Microscopy and Spectroscopy Team, Korea Basic Science Institute, Ochang, Cheongju, Chungbuk, Republic of Korea.
  • 5 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 6 Electron Microscopy Research Center, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea; Electron Microscopy and Spectroscopy Team, Korea Basic Science Institute, Daejeon, Republic of Korea.
  • 7 Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea. Electronic address: yunlee@snu.ac.kr.
PMID: 36754021 DOI: 10.1016/j.cmet.2023.01.003
Abstract

Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.

Keywords

FIS1; M1; OPA1; donut mitochondria; mitochondria; mitochondrial secretion; mitochondrial transplantation; mitochondrial-derived vesicles; osteoblasts; osteogenesis.

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