Dissecting the dual role of ATAD3A in nucleoid stability and cristae ultrastructure.
G. Rigoni1, A. Mehrotra1, E. Calvo4, C. Glytsou1, F. Caicci1, M. Noguchi1, M. Sturlese2, S. Moro2, N. Isihara5, C. Romualdi1, J. Vazquez4, J.A. Enriquez 4, L. Scorrano1,3 and M.E.Soriano1
1Department of Biology; University of Padova 35121, Italy
2Department of Pharmaceutical Sciences; University of Padova 35121, Italy
3Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova 35129, Italy
4Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain
5Department of Protein Biochemistry, Kurume University, Japan
The regulation of mitochondrial dynamics and ultrastructure is crucial for cell function and viability. A well-characterized regulator of such processes is the inner mitochondrial membrane GTPase OPA1, which forms high molecular weight (HMW) complexes that maintain cristae ultrastructure and thus restrict cytochrome c to the cristae lumen. Our proteomic analysis of OPA1-HMW complexes has enabled the identification of proteins that potentially interact with OPA1 during apoptotic cristae remodeling. Among these, ATAD3A stands out as one of the most promising OPA1 interactors, data confirmed by coimmunoprecipitation experiments. Our studies demonstrate that ATAD3A regulates cristae biogenesis and stability. The formation or disruption of ATAD3 oligomers results in narrow or swollen cristae, respectively. We also show that ATAD3A oligomers are not required for cristae biogenesis, but instead are likely involved in nucleoid and mtDNA stability. Indeed, inhibiting ATAD3 oligomerization results in the disruption of a specific protein complex that we have identified to depend on the presence of mtDNA and of which ATAD3A is a component.
Our studies with ATAD3A mutants identify the critical domains implicated in cristae formation and mtDNA stability, supporting a dual role of ATAD3A in mitochondrial function.