Abstract
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.
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•Neurons show mitochondrial cristae abnormalities early when ATAD3 is knocked out•Oxidative phosphorylation abnormalities are secondary•ATAD3 interacts with several inner mitochondrial membrane proteins•ATAD3 is regularly spaced within mitochondrial membranes
Arguello et al. show that deletion of the mitochondrial protein ATAD3 in neurons leads to neuronal loss and death. The earliest phenotype is disruption of the mitochondrial inner membrane structure; OXPHOS complexes are affected later. ATAD3 is regularly spaced and has several interactors at the inner membrane, including CI subunits.
