title: Down-regulation of mortalin exacerbates Aβ-mediated mitochondrial fragmentation and dysfunction.
abstract: 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.
authors: From the Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 446-701, South Korea.
authors: So Jung
authors: SJ
authors: Park
authors: Ji Hyun
authors: JH
authors: Shin
authors: Jae In
authors: JI
authors: Jeong
authors: Ji Hoon
authors: JH
authors: Song
authors: Yoon Kyung
authors: YK
authors: Jo
authors: Eun Sung
authors: ES
authors: Kim
authors: Eunjoo H
authors: EH
authors: Lee
authors: Jung Jin
authors: JJ
authors: Hwang
authors: Eun Kyung
authors: EK
authors: Lee
authors: Sun Ju
authors: SJ
authors: Chung
authors: Jae-Young
authors: JY
authors: Koh
authors: Dong-Gyu
authors: DG
authors: Jo
authors: Dong-Hyung
authors: DH
authors: Cho
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; C083794:Hspa9 protein, mouse
keywords: Alzheimers Disease; Amyloid-β; Cell Death; Drp1; Mitochondria; Mitochondrial Apoptosis; Mitochondrial Fission; Mortalin; Neurodegenerative Diseases