Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells.
Dev Biol
; 391(2): 230-40, 2014 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-24780625
ABSTRACT
Mutations in the Huntington locus (htt) have devastating consequences. Gain-of-poly-Q repeats in Htt protein causes Huntington's disease (HD), while htt(-/-) mutants display early embryonic lethality. Despite its importance, the function of Htt remains elusive. To address this, we compared more than 3700 compounds in three syngeneic mouse embryonic stem cell (mESC) lines htt(-/-), extended poly-Q (Htt-Q140/7), and wild-type mESCs (Htt-Q7/7) using untargeted metabolite profiling. While Htt-Q140/7 cells did not show major differences in cellular bioenergetics, we find extensive metabolic aberrations in htt(-/-) mESCs, including (i) complete failure of ATP production despite preservation of the mitochondrial membrane potential; (ii) near-maximal glycolysis, with little or no glycolytic reserve; (iii) marked ketogenesis; (iv) depletion of intracellular NTPs; (v) accelerated purine biosynthesis and salvage; and (vi) loss of mitochondrial structural integrity. Together, our findings reveal that Htt is necessary for mitochondrial structure and function from the earliest stages of embryogenesis, providing a molecular explanation for htt(-/-) early embryonic lethality.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Nucleares
/
Metabolismo Energético
/
Células Madre Embrionarias
/
Metaboloma
/
Mitocondrias
/
Proteínas del Tejido Nervioso
Límite:
Animals
Idioma:
En
Revista:
Dev Biol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos