Reduced levels of mitochondrial complex I subunit NDUFB8 and linked complex I + III oxidoreductase activity in the TgCRND8 mouse model of Alzheimer's disease.
Bioenergetic failure is a feature of Alzheimer's disease (AD). We examined mitochondrial function in the amyloid-β protein precursor transgenic 'TgCRND8' mouse model of AD. Activities of NADH: cytochrome c reductase (complex I + III) and cytochrome oxidase (complex IV) of the electron transport chain, as well as those of α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH) were assessed in brains of 45 week-old mice. Complex I + III activity was reduced by almost 50%, whereas complex IV, α-KGDH, and PDH activities were unaffected. Reduced activity coincided with decreased expression of NDUFB8, a nuclear-DNA encoded subunit integral to the assembly of complex I. The composition and availability of cardiolipin, a major phospholipid in inner mitochondrial membranes, was not altered. To determine whether mitochondrial output is affected by the selective reduction in complex I + III activity, we examined tissue levels of high-energy phosphates. ATP was maintained whereas creatine increased in the cortex and hippocampus. These results suggest disruption of complex I function and the likely role of creatine in sustaining ATP at late stages of dysfunction in TgCRND8 mice.
Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, Canada Department of Physiology, University of Toronto, Toronto, ON, Canada.
Beverly M
BM
Francis
Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, Canada.
Jimao
J
Yang
Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
Byung Jun
BJ
Song
Departments of Biochemistry and Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.
Saurabh
S
Gupta
Departments of Biochemistry and Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.
Mary
M
Maj
Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
Richard P
RP
Bazinet
Departments of Biochemistry and Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.
Brian
B
Robinson
Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, Canada Department of Physiology, University of Toronto, Toronto, ON, Canada Department of Medicine, Division Neurology, University of Toronto, Toronto, ON, Canada.
Howard T J
HT
Mount
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D002308:Cardiolipins; C000592481:NDUFB8 protein, mouse; D011768:Pyruvate Dehydrogenase Complex; D000255:Adenosine Triphosphate; D007655:Ketoglutarate Dehydrogenase Complex; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D003401:Creatine
ATP; Alzheimer's disease; NDUFB8; amyloid; cardiolipin; creatine; electron transport chain