ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly

The ATPase Family AAA Domain Containing 3A (ATAD3A), is a mitochondrial inner membrane protein conserved in metazoans. ATAD3A has been associated with several mitochondrial functions, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. To address its primary role, we generated a neuronal-specific conditional knockout (Atad3 nKO) mouse model, which developed a severe encephalopathy by 5 months of age. Pre-symptomatic mice showed aberrant mitochondrial cristae morphogenesis in the cortex as early as 2 months. Using a multi-omics approach in the CNS of 2-to-3-month-old mice, we found early alterations in the organelle membrane structure. We also show that human ATAD3A associates with different components of the inner membrane, including OXPHOS complex I, Letm1, and prohibitin complexes. Stochastic Optical Reconstruction Microscopy (STORM) shows that ATAD3A is regularly distributed along the inner mitochondrial membrane, suggesting a critical structural role in inner mitochondrial membrane and its organization, most likely in an ATPase-dependent manner.

Automated summary

ATAD3A is a mitochondrial inner membrane protein that plays a critical role in mitochondrial function, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. Its neuronal-specific knockout in mice can lead to severe encephalopathy, associated with aberrant mitochondrial membrane structure changes. The protein is regularly distributed along the inner mitochondrial membrane, suggesting a structural role in membrane organization in an ATPase-dependent manner.