Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer's disease: On defects in the cytochrome c oxidase complex and aldehyde detoxification

Issue title: Mitochondria in Alzheimer's Disease

Guest editors: Paula I. Moreirax and Catarina Oliveiray

Article type: Research Article

Authors: Ohta, Shigeo^{; *} | Ohsawa, Ikuroh

Affiliations: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki-city, Kanagawa-pref., 211-8533 Japan | [x] Center for Neuroscience and Cell Biology, Institute of Physiology – Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal | [y] Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal

Correspondence: [*] Corresponding author. Fax: +81 44 733 9268; E-mail: [email protected].

Abstract: The mitochondrion is an organelle that plays a central role in energy production. It, at the same time, generates reactive oxygen species as by-products. Large-scale epidemiological case-control studies suggest the involvements of dihydrolipoamide succinyltransferase (DLST) of the mitochondrial Krebs cycle and mitochondrial aldehyde dehydrogenase-2 (ALDH2) in Alzheimer's disease (AD). The DLST gene has two gene-products, one of which, a novel gene product MIRTD, mediates the molecular assembly of the cytochrome c oxidase complex whose defect has been a candidate of the causes of AD. Since levels of MIRTD mRNA in the brains of AD patients were significantly low, a decrease in MIRTD could affect energy production. ALDH2, a matrix enzyme, was found to act as a protector against oxidative stress through oxidizing toxic aldehydes, such as 4-hydroxy-2-nonenal, that are spontaneously produced from lipid peroxides. Hence, a decrease in ALDH2 activity is proposed to contribute to AD. Indeed, transgenic mice with low activity of ALDH2 exhibited an age-dependent neurodegeneration accompanying memory loss. Since amyloid β peptide has been recently shown to be present in neuronal mitochondria to decline energy production and enhance ROS production, it has become possible to link AD more closely with roles of mitochondria in the pathogenesis.

Keywords: Aldehyde, ALDH2, case-control study, cytochrome c oxidase, DLST

DOI: 10.3233/JAD-2006-9208

Journal: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 155-166, 2006