Reduced Levels of Mitochondrial Complex I Subunit NDUFB8 and Linked Complex I + III Oxidoreductase Activity in the TgCRND8 Mouse Model of Alzheimer's Disease

Article type: Research Article

Authors: Francis, Beverly M.^{a; b} | Yang, Jimao^a | Song, Byung Jun^c | Gupta, Saurabh^d | Maj, Mary^d | Bazinet, Richard P.^c | Robinson, Brian^d | Mount, Howard T.J.^{a; b; e; *}

Affiliations: [a] Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, Canada | [b] Department of Physiology, University of Toronto, Toronto, ON, Canada | [c] Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada | [d] Departments of Biochemistry and Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada | [e] Department of Medicine, Division Neurology, University of Toronto, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Dr. Howard T.J. Mount, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada. Tel.: +1 416 978 1874; Fax: +1 416 978 1878; E-mail: [email protected].

Abstract: 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.

Keywords: Alzheimer's disease, amyloid, ATP, cardiolipin, creatine, electron transport chain, NDUFB8

DOI: 10.3233/JAD-131499

Journal: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 347-355, 2014