The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes.
Dynamic interactions between components of the outer (OM) and inner (IM) membranes control a number of critical mitochondrial functions such as channeling of metabolites and coordinated fission and fusion. We identify here the mitochondrial AAA(+) ATPase protein ATAD3A specific to multicellular eukaryotes as a participant in these interactions. The N-terminal domain interacts with the OM. A central transmembrane segment (TMS) anchors the protein in the IM and positions the C-terminal AAA(+) ATPase domain in the matrix. Invalidation studies in Drosophila and in a human steroidogenic cell line showed that ATAD3A is required for normal cell growth and cholesterol channeling at contact sites. Using dominant-negative mutants, including a defective ATP-binding mutant and a truncated 50-amino-acid N-terminus mutant, we showed that ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery. The capacity of ATAD3A to impact essential mitochondrial functions and organization suggests that it possesses unique properties in regulating mitochondrial dynamics and cellular functions in multicellular organisms.
INSERM Unité 873/TS-iRTSV, CEA Grenoble, 38054 Grenoble Cedex 9, France.
Benoît
B
Gilquin
Emmanuel
E
Taillebourg
Nadia
N
Cherradi
Arnaud
A
Hubstenberger
Olivia
O
Gay
Nicolas
N
Merle
Nicole
N
Assard
Marie-Odile
MO
Fauvarque
Shiho
S
Tomohiro
Osamu
O
Kuge
Jacques
J
Baudier
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D006801:Humans; D008565:Membrane Proteins; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques
C549686:ATAD3A protein, human; C519737:ATAD3B protein, human; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities