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Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged

June Heo1,2, Yeon-Ji Park1, Yonghyeon Kim1,2

  • 1Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, South Korea.

Cell Death & Disease
|December 1, 2023
PubMed

Insights

Mitochondrial DNA breaks trigger immune responses via DNA-PKcs. Mitochondrial E3 ligase MARCH5 degrades DNA-PKcs, preventing prolonged inflammation and safeguarding against chronic inflammatory reactions.

Area of Science:

  • Cellular Biology
  • Immunology
  • Mitochondrial Biology

Background:

  • Mitochondrial dysfunction is implicated in chronic degenerative diseases.
  • Aberrant immune responses to cytoplasmic mitochondrial DNA (mtDNA) may contribute to these conditions.

Purpose of the Study:

  • To investigate the role of mitochondrial DNA double-strand breaks (mtDSBs) in innate immune responses.
  • To identify key molecular players regulating the inflammatory cascade initiated by mtDSBs.

Main Methods:

  • Development of mtDNA-targeted endonuclease systems (MTERF1-FokI, TFAM-FokI) to induce mtDSBs.
  • Utilized cGAS knockout cells and RAW264.7 macrophage cells.
  • Assessed interferon production, DNA-PKcs activation, HSPA8 phosphorylation, and MARCH5-mediated protein degradation.

Main Results:

  • mtDSB induction reduced mtDNA copy number and activated DNA-PKcs and HSPA8 in a VDAC1-dependent manner.
  • MARCH5 degraded DNA-PKcs, thereby reducing type I interferon response.
  • LPS-induced mitochondrial damage increased phospho-HSPA8 and mIFNB1 mRNA synthesis in a DNA-PKcs-dependent manner, which was prolonged in March5 knockout macrophages.

Conclusions:

  • Cytoplasmic mtDNA triggers a cellular immune response mediated by DNA-PKcs.
  • Mitochondrial MARCH5 acts as a crucial regulator, preventing persistent inflammation by degrading DNA-PKcs and limiting inflammatory reactions.

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