ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects

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.

Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism

“…6 ATAD3 has also been shown to interact with mitochondrial nucleoprotein complexes and to play roles in mtDNA organization and replication. 2,7,8 More recently it has been shown to interact with Drp1/DNM1L to support Drp1-induced mitochondrial division, 9 a process that drives mtDNA segregation. 10,11 Concordantly, ATAD3 dysfunction and deficiency have a wide range of effects on mitochondrial structure and function, characterized by disturbed mitochondrial morphology and fission dynamics, 3,6 loss of cristae, 12 perturbed mtDNA and cholesterol metabolism, impaired mitochondrial steroidogenesis, 2,13 and decreased levels of some mitochondrial oxidative phosphorylation (OXPHOS) components.…”

A splice variant in ATAD3A expands the clinical and genetic spectrum of Harel-Yoon syndrome

“…ATAD3A is a mitochondrial AAA + ATPase protein localized between the inner and outer mitochondrial membrane 1 ; its role includes the stabilization of mitochondrial DNA, the regulation of mitochondrial fission/fusion, and the regulation of cholesterol homeostasis. 1,2 Harel-Yoon syndrome (HYS) can result from biallelic deletions in the ATAD3 gene cluster (containing ATAD3A, ATAD3B, and ATAD3C) and is associated with cerebellar and brainstem atrophy, hypotonia, encephalopathy, and death in the first days and weeks of life. 3,4 A less severe presentation has been reported in those with biallelic missense variants.…”

Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases

“…With a PolyQ expansion at the N terminus, the mutant Huntington protein (mtHtt) has a toxic function causing neuronal death, particularly in the striatum and progressively in other parts of the brain (Ferrante et al, 1991;Andrews et al, 1999;Williams and Paulson, 2008). Mitochondrial dysfunction has been demonstrated to be strongly correlated with HD, and dysregulation of mitochondrial dynamics plays a key role in the development of HD (Johri et al, 2013;Zhao et al, 2019).…”