Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse.
The anorectic anx/anx mouse exhibits disturbed feeding behavior and aberrances, including neurodegeneration, in peptidergic neurons in the appetite regulating hypothalamic arcuate nucleus. Poor feeding in infants, as well as neurodegeneration, are common phenotypes in human disorders caused by dysfunction of the mitochondrial oxidative phosphorylation system (OXPHOS). We therefore hypothesized that the anorexia and degenerative phenotypes in the anx/anx mouse could be related to defects in the OXPHOS. In this study, we found reduced efficiency of hypothalamic OXPHOS complex I assembly and activity in the anx/anx mouse. We also recorded signs of increased oxidative stress in anx/anx hypothalamus, possibly as an effect of the decreased hypothalamic levels of fully assembled complex I, that were demonstrated by native Western blots. Furthermore, the Ndufaf1 gene, encoding a complex I assembly factor, was genetically mapped to the anx interval and found to be down-regulated in anx/anx mice. These results suggest that the anorexia and hypothalamic neurodegeneration of the anx/anx mouse are associated with dysfunction of mitochondrial complex I.
Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
Charlotte
C
Lindfors
Ida A K
IA
Nilsson
Pablo M
PM
Garcia-Roves
Aamir R
AR
Zuberi
Mohsen
M
Karimi
Leah Rae
LR
Donahue
Derry C
DC
Roopenian
Jan
J
Mulder
Mathias
M
Uhlén
Tomas J
TJ
Ekström
Muriel T
MT
Davisson
Tomas G M
TG
Hökfelt
Martin
M
Schalling
Jeanette E
JE
Johansen
D000483:Alleles; D000818:Animals; D000855:Anorexia / Q000235:genetics / Q000503:physiopathology*; D007031:Hypothalamus / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress