ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects.
Nat Commun
; 10(1): 1371, 2019 03 26.
Article
en En
| MEDLINE
| ID: mdl-30914652
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.
Texto completo:
1
Bases de datos:
MEDLINE
Métodos Terapéuticos y Terapias MTCI:
Terapias_energeticas
/
Bioenergetica
Asunto principal:
Enfermedad de Huntington
/
Proteínas Mitocondriales
/
Metabolismo Energético
/
Dinámicas Mitocondriales
/
ATPasas Asociadas con Actividades Celulares Diversas
/
Proteínas de la Membrana
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Idioma:
En
Revista:
Nat Commun
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos