HOXC13-driven TIMM13 overexpression promotes osteosarcoma cell growth

Cell Death Dis. 2023 Jul 5;14(7):398. doi: 10.1038/s41419-023-05910-0.

Abstract

TIMM13 (translocase of inner mitochondrial membrane 13) located at the mitochondrial intermembrane space is vital for the integrity and function of mitochondria. We found that the mitochondrial protein TIMM13 is upregulated in human OS tissues and cells. In patient-derived primary OS cells and established cell lines, TIMM13 shRNA or knockout provoked mitochondrial dysfunction, causing mitochondrial depolarization, reactive oxygen species production, and oxidative injury, as well as lipid peroxidation, DNA damage, and ATP depletion. Moreover, TIMM13 depletion provoked OS cell apoptosis and inhibited cell proliferation and migration. Conversely, ectopic TIMM13 overexpression increased ATP contents, enhancing OS cell proliferation and migration. Moreover, we discovered that Akt-mTOR activation was inhibited with TIMM13 depletion in primary OS cells. Further studies revealed that HOXC13 (Homeobox C13)-dependent TIMM13 transcription was significantly increased in OS tissues and cells. Whereas TIMM13 transcription and expression were decreased following HOXC13 silencing in primary OS cells. In vivo, TIMM13 KO potently inhibited OS xenograft growth in the proximal tibia of nude mice. TIMM13 KO also induced Akt-mTOR inactivation, ATP depletion, oxidative injury, and apoptosis in the in situ OS tumors. Together, upregulation of the mitochondrial protein TIMM13 is important for OS cell growth, representing a novel and promising therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Apoptosis / genetics
  • Bone Neoplasms* / genetics
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation / genetics
  • Homeodomain Proteins
  • Humans
  • Mice
  • Mice, Nude
  • Mitochondrial Proteins
  • Osteosarcoma* / pathology
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases / genetics
  • Transcription Factors / therapeutic use

Substances

  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Transcription Factors
  • Mitochondrial Proteins
  • Adenosine Triphosphate
  • HOXC13 protein, human
  • Homeodomain Proteins