ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels

Mutations in the mitochondrial inner membrane ATPase ATAD3A result in neurological syndromes in humans. In mice, the ubiquitous disruption of Atad3 was embryonic lethal, but a skeletal muscle specific conditional knockout (cKO) was viable. At birth, ATAD3 muscle cKO mice had normal weight, but from 2 months onwards showed progressive motor-impaired coordination and weakness. Loss of ATAD3 caused early and severe mitochondrial structural abnormalities, mitochondrial proliferation and muscle atrophy. There was dramatic reduction in mitochondrial cristae junctions and overall cristae morphology. The lack of mitochondrial cristae was accompanied by a reduction in high molecular weight MICOS complexes, and to a lesser extent in OPA1. Moreover, muscles lacking ATAD3 showed altered cholesterol metabolism, accumulation of mtDNA replication intermediates, progressive mitochondrial DNA depletion and deletions. Unexpectedly, decreases in the levels of some OXPHOS components occurred after cristae destabilization, indicating that ATAD3 is not critical for mitochondrial translation, as previously suggested. Our results showed a critical early role of ATAD3 in regulating mitochondrial inner membrane structure, leading to secondary defects in mtDNA replication and complex V and cholesterol levels in a post-mitotic tissue.