"ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane"

Free Radic Biol Med. 2024 Feb 1:211:114-126. doi: 10.1016/j.freeradbiomed.2023.12.006. Epub 2023 Dec 12.


Mitochondrial ATAD3A is an ATPase Associated with diverse cellular Activities (AAA) domain containing enzyme, involved in the structural organization of the inner mitochondrial membrane and of increasing importance in childhood disease. In humans, two ATAD3A paralogs arose by gene duplication during evolution: ATAD3B and ATAD3C. Here we investigate the cellular activities of the ATAD3C paralog that has been considered a pseudogene. We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space. Overexpression of ATAD3C, but not of ATAD3A, in fibroblasts caused a decrease in cell proliferation and oxygen consumption rate, and an increase of cellular ROS. This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size. Consistent with a negative regulation of ATAD3A function in mitochondrial membrane organization, ATAD3C expression led to increased accumulation of respiratory chain dimeric CIII in the inner membrane, to the detriment to that assembled in respiratory supercomplexes. Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell.

Keywords: ATAD3A; ATAD3B; ATAD3C; Mitochondria; OXPHOS; Respiratory complexes; Respiratory supercomplexes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / chemistry
  • ATPases Associated with Diverse Cellular Activities / genetics
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Adenosine Triphosphatases* / genetics
  • Adenosine Triphosphatases* / metabolism
  • Gene Duplication
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Membranes* / metabolism
  • Mitochondrial Proteins / metabolism


  • Adenosine Triphosphatases
  • ATAD3A protein, human
  • ATPases Associated with Diverse Cellular Activities
  • Membrane Proteins
  • Mitochondrial Proteins
  • ATAD3C protein, human