TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA

Nat Cell Biol. 2024 Jun;26(6):878-891. doi: 10.1038/s41556-024-01419-6. Epub 2024 May 23.


When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.

MeSH terms

  • Animals
  • Autophagy*
  • Cytoplasm / metabolism
  • DNA, Mitochondrial* / genetics
  • DNA, Mitochondrial* / metabolism
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • HEK293 Cells
  • High Mobility Group Proteins
  • Humans
  • Inflammation* / genetics
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Lysosomes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Mitochondrial Proteins* / genetics
  • Mitochondrial Proteins* / metabolism
  • Protein Binding
  • Signal Transduction
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism


  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • Transcription Factors
  • Microtubule-Associated Proteins
  • TFAM protein, human
  • MAP1LC3A protein, human
  • Tfam protein, mouse
  • High Mobility Group Proteins