2. Mitochondria and Niemann Pick disease
Until relatively recently, dogma had it that mitochondria do not
contain cholesterol. Now we know that mitochondrial
membranes both contain this lipid and that the organelle
metabolizes it. The work of Yu et al below shows that the
amount of cholesterol is significantly elevated within
mitochondrial membranes of Niemann Pick Disease C1 type
(NPC1) mouse brain and neurons Also, there is a decreased
ATP synthase activity and reduced mitochondrial membrane
potential. Reducing the level of cholesterol with the drug
methyl-SS-cyclodextrin restored ATP synthase activity.
The authors argue that ATP deficiency induced by altered
cholesterol metabolism in mitochondria explains the neuronal
impairment in NPC1 disease.
YU.W, GONG.JS, KO.M, GARVER.WS, YANAGISAWA.K &
MICHIKAWA. M. J BIOL CHEM 280. 11731-9 (2005)
Altered Cholesterol Metabolism in Niemann-Pick Type C1 Mouse Brains Affects Mitochondrial Function*
Wenxin Yu , Jian-Sheng Gong , Mihee Ko , William S. Garver , Katsuhiko Yanagisawa , and Makoto Michikawa||
From the Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan, The Pharmaceuticals and Medical Devices Agency, Tokyo 100-0013, Japan, and the Department of Pediatrics, The University of Arizona, Tucson, Arizona 85724
Niemann-Pick type C1 (NPC1) disease is a fatal hereditary disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. Although the NPC1 gene has been identified, the molecular mechanism responsible for neuronal dysfunction in brains of patients with NPC1 disease remains unknown. This study demonstrates that the amount of cholesterol within mitochondria membranes is significantly elevated in NPC1 mouse brains and neural cells. In addition, the mitochondrial membrane potential, the activity of ATP synthase, and henceforth the level of ATP are markedly decreased in NPC1 mouse brains and neurons. Importantly, reducing the level of cholesterol within mitochondrial membranes using methyl--cyclodextri n can restore the activity of ATP synthase. Finally, NPC1 neurons show an impaired neurite outgrowth, which can be rescued by exogenous ATP. These results suggest that mitochondrial dysfunctions and subsequent ATP deficiency, which are induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC1 disease.