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

Abstract

Mutations in the mitochondrial inner membrane ATPase result in neurological syndromes in humans. In mice, the ubiquitous disruption of (also known as ) was embryonic lethal, but a skeletal muscle-specific conditional knockout (KO) was viable. At birth, ATAD3 muscle KO mice had normal weight, but from 2 months onwards they 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 mitochondrial contact site and cristae organizing system (MICOS) complexes, and to a lesser extent in OPA1. Moreover, muscles lacking ATAD3 showed altered cholesterol metabolism, accumulation of mitochondrial DNA (mtDNA) replication intermediates, progressive mtDNA depletion and deletions. Unexpectedly, decreases in the levels of some OXPHOS components occurred after cristae destabilization, indicating that ATAD3 is not crucial for mitochondrial translation, as previously suggested. Our results show 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 postmitotic tissueThis article has an associated First Person interview with the first author of the paper.

Mitochondrial Morphofunction in Mammalian Cells

“…sorting and assembly machinery (SAM; MIC60 interaction), (iii) the protein translocase of the MOM (TOM; MIC60 interaction), (iv) the presequence translocase of the MIM (TIM23), (v) mtDNA, (vi) the ETC, and (vii) CV (352). Recent evidence suggests that MICOS also interacts with the MIM ATPase ATAD3A, and that the latter protein assists in stabilizing mitochondrial cristae, potentially via interactions with the MOM (307). Subunit MIC10 plays a central role in the yeast MICOS system (31), and MIC10 oligomerization induces MOM bending at CJs (17).…”

Metabolic implications of organelle–mitochondria communication

“…Proteins whose depletion alters lipid metabolism Skeletal muscle-specific Atad3 knockout mice show muscle atrophy in combination with mitochondrial abnormalities that include lack of cristae, reduced OXPHOS complexes and OPA1 expression, and progressive mtDNA depletion [198]. Fibroblasts derived from patients suffering from ATAD3 gene cluster deletions show impaired cholesterol metabolism and mtDNA damage, as well as impaired lipid metabolism [199] (Fig 4D).…”

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus that are Necessary for Synapse Function

“…We used antibodies against CPT1 and ATAD3A to test association of molecules involved in mitochondrial lipid metabolism with SLC25A1 ( Fig. 2E) (Bennett and Santani, 1993;Peralta et al, 2018;Rone et al, 2012). FLAG antibodies precipitated MRPL11, CPT1 and ATAD3A ( Fig.…”