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ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects
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ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects
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Journal Article
ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects
2019
Overview
Mitochondrial fragmentation and bioenergetic failure manifest in Huntington’s disease (HD), a fatal neurodegenerative disease. The factors that couple mitochondrial fusion/fission with bioenergetics and their impacts on neurodegeneration however remain poorly understood. Our proteomic analysis identifies mitochondrial protein ATAD3A as an interactor of mitochondrial fission GTPase, Drp1, in HD. Here we show that, in HD, ATAD3A dimerization due to deacetylation at K135 residue is required for Drp1-mediated mitochondrial fragmentation. Disturbance of ATAD3A steady state impairs mtDNA maintenance by disrupting TFAM/mtDNA binding. Blocking Drp1/ATAD3A interaction with a peptide, DA1, abolishes ATAD3A oligomerization, suppresses mitochondrial fragmentation and mtDNA lesion, and reduces bioenergetic deficits and cell death in HD mouse- and patient-derived cells. DA1 treatment reduces behavioral and neuropathological phenotypes in HD transgenic mice. Our findings demonstrate that ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance, suggesting that DA1 might be useful for developing HD therapeutics.
Huntington’s disease leads to mitochondrial fragmentation and bioenergetic failure, although how the two events are connected is poorly understood. Here, Zhao et al. identify ATAD3A as a molecular linker and show that a peptide inhibitor of ATAD3A oligomerization suppresses HD phenotypes.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/89
/ 64/110
/ 96/95
/ Animals
/ ATPases Associated with Diverse Cellular Activities - genetics
/ ATPases Associated with Diverse Cellular Activities - metabolism
/ DNA, Mitochondrial - metabolism
/ DNA-Binding Proteins - metabolism
/ Energy Metabolism - genetics
/ Fission
/ GTP Phosphohydrolases - metabolism
/ High Mobility Group Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Huntington Disease - genetics
/ Huntington Disease - metabolism
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Microtubule-Associated Proteins - metabolism
/ Mitochondrial Dynamics - genetics
/ Mitochondrial Proteins - genetics
/ Mitochondrial Proteins - metabolism
/ Mutation
/ Proteins
/ Science
