title: Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults.
abstract: Neurons rely heavily on mitochondria for their function and survival. Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease. PGC-1α is a master regulator of mitochondrial biogenesis and function. Here we identify necdin as a potent PGC-1α stabilizer that promotes mitochondrial biogenesis via PGC-1α in mammalian neurons. Expression of genes encoding mitochondria-specific proteins decreases significantly in necdin-null cortical neurons, where mitochondrial function and expression of the PGC-1α protein are reduced. Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. Moreover, overexpression of necdin in the substantia nigra in vivo of adult mice protects dopaminergic neurons against degeneration in experimental Parkinson's disease. These data reveal that necdin promotes mitochondrial biogenesis through stabilization of endogenous PGC-1α to exert neuroprotection against mitochondrial insults.
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Shiraishi
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kazushiro
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Department of Neurology, Pathology and Cell Biology, Columbia University, New York, New York, 10032, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Hideki
authors.identifier: http://orcid.org/0000-0002-0874-7542
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000166:cytology; D004272:DNA, Mitochondrial; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D001678:Organelle Biogenesis; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D055550:Protein Stability; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C069766:necdin