Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATPases Associated with Diverse Cellular Activities / genetics*
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ATPases Associated with Diverse Cellular Activities / metabolism
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Animals
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Cell Death
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Cell Line
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DNA, Mitochondrial / metabolism
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DNA-Binding Proteins / metabolism
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Dynamins / metabolism
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Energy Metabolism / genetics*
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GTP Phosphohydrolases / metabolism
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Gene Knockdown Techniques
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HEK293 Cells
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High Mobility Group Proteins / metabolism
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Humans
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Huntington Disease / genetics*
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Huntington Disease / metabolism
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Microtubule-Associated Proteins / metabolism
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Mitochondrial Dynamics / genetics*
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Mitochondrial Proteins / genetics*
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Mitochondrial Proteins / metabolism
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Mutation
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Neurons / metabolism
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Proteomics
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Transcription Factors / metabolism
Substances
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ATAD3A protein, human
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Atad3a protein, mouse
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DNA, Mitochondrial
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DNA-Binding Proteins
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High Mobility Group Proteins
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Membrane Proteins
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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TFAM protein, human
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Tfam protein, mouse
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Transcription Factors
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GTP Phosphohydrolases
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ATPases Associated with Diverse Cellular Activities
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DNM1L protein, human
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Dnm1l protein, mouse
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Dynamins