Down-regulation of mortalin exacerbates Aβ-mediated mitochondrial fragmentation and dysfunction

• Published in: The Journal of biological chemistry Vol. 289; no. 4; pp. 2195 - 2204
• Main Authors: Park, So Jung, Shin, Ji Hyun, Jeong, Jae In, Song, Ji Hoon, Jo, Yoon Kyung, Kim, Eun Sung, Lee, Eunjoo H, Hwang, Jung Jin, Lee, Eun Kyung, Chung, Sun Ju, Koh, Jae-Young, Jo, Dong-Gyu, Cho, Dong-Hyung
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 24-01-2014
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animals; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cell Death - genetics; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; HSP70 Heat-Shock Proteins - biosynthesis; HSP70 Heat-Shock Proteins - genetics; Humans; Mice; Mice, Transgenic; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Neurobiology; Neurodegenerative Diseases; Mitochondria; Mortalin; Mitochondrial Apoptosis; Alzheimers Disease; Mitochondrial Fission; Cell Death; Amyloid-β; Drp1
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.492587

Mitochondrial dynamics greatly influence the biogenesis and morphology of mitochondria. Mitochondria are particularly important in neurons, which have a high demand for energy. Therefore, mitochondrial dysfunction is strongly associated with neurodegenerative diseases. Until now various post-translational modifications for mitochondrial dynamic proteins and several regulatory proteins have explained complex mitochondrial dynamics. However, the precise mechanism that coordinates these complex processes remains unclear. To further understand the regulatory machinery of mitochondrial dynamics, we screened a mitochondrial siRNA library and identified mortalin as a potential regulatory protein. Both genetic and chemical inhibition of mortalin strongly induced mitochondrial fragmentation and synergistically increased Aβ-mediated cytotoxicity as well as mitochondrial dysfunction. Importantly we determined that the expression of mortalin in Alzheimer disease (AD) patients and in the triple transgenic-AD mouse model was considerably decreased. In contrast, overexpression of mortalin significantly suppressed Aβ-mediated mitochondrial fragmentation and cell death. Taken together, our results suggest that down-regulation of mortalin may potentiate Aβ-mediated mitochondrial fragmentation and dysfunction in AD.