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

Author:

Peralta Susana1,Goffart Steffi2,Williams Sion L.1,Diaz Francisca1,Garcia Sofia1ORCID,Nissanka Nadee3,Area-Gomez Estela4,Pohjoismäki Jaakko2,Moraes Carlos T.135ORCID

Affiliation:

1. Department of Neurology, University of Miami Miller School of Medicine, Miami FL, USA

2. Department of Environmental and Biological Sciences, University of Eastern Finland; Joensuu, Finland

3. Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami FL, USA

4. Department of Neurology. Columbia University Medical Center. New York, NY, USA

5. Department of Cell Biology, University of Miami Miller School of Medicine, Miami FL, USA

Abstract

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.

Funder

National Institute of Neurological Disorders and Stroke

National Institute on Aging

National Eye Institute

Publisher

The Company of Biologists

Subject

Cell Biology

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