ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects

Yuanyuan Zhao, Xiaoyan Sun, Di Hu, Domenick A. Prosdocimo, Charles Hoppel, Mukesh K. Jain, Rajesh Ramachandran and Xin Qi ()
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Yuanyuan Zhao: Case Western Reserve University School of Medicine
Xiaoyan Sun: Case Western Reserve University School of Medicine
Di Hu: Case Western Reserve University School of Medicine
Domenick A. Prosdocimo: Case Western Reserve University School of Medicine
Charles Hoppel: Case Western Reserve University School of Medicine
Mukesh K. Jain: Case Western Reserve University School of Medicine
Rajesh Ramachandran: Case Western Reserve University School of Medicine
Xin Qi: Case Western Reserve University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09291-x

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