PGC-1{alpha} and PGC-1{beta} regulate mitochondrial density in neurons.
Recent studies indicate that regulation of cellular oxidative capacity through enhancing mitochondrial biogenesis may be beneficial for neuronal recovery and survival in human neurodegenerative disorders. The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been shown to be a master regulator of mitochondrial biogenesis and cellular energy metabolism in muscle and liver. The aim of our study was to establish whether PGC-1alpha and PGC-1beta control mitochondrial density also in neurons and if these coactivators could be up-regulated by deacetylation. The results demonstrate that PGC-1alpha and PGC-1beta control mitochondrial capacity in an additive and independent manner. This effect was observed in all studied subtypes of neurons, in cortical, midbrain, and cerebellar granule neurons. We also observed that endogenous neuronal PGC-1alpha but not PGC-1beta could be activated through its repressor domain by suppressing it. Results demonstrate also that overexpression of SIRT1 deacetylase or suppression of GCN5 acetyltransferase activates transcriptional activity of PGC-1alpha in neurons and increases mitochondrial density. These effects were mediated exclusively via PGC-1alpha, since overexpression of SIRT1 or suppression of GCN5 was ineffective where PGC-1alpha was suppressed by short hairpin RNA. Moreover, the results demonstrate that overexpression of PGC-1beta or PGC-1alpha or activation of the latter by SIRT1 protected neurons from mutant alpha-synuclein- or mutant huntingtin-induced mitochondrial loss. These evidences demonstrate that activation or overexpression of the PGC-1 family of coactivators could be used to compensate for neuronal mitochondrial loss and suggest that therapeutic agents activating PGC-1 would be valuable for treating neurodegenerative diseases in which mitochondrial dysfunction and oxidative damage play an important pathogenic role.
Wareski
Przemyslaw
P
Department of Pharmacology, University of Tartu, Ravila 19, 51014 Tartu, Estonia.
Vaarmann
Annika
A
Choubey
Vinay
V
Safiulina
Dzhamilja
D
Liiv
Joanna
J
Kuum
Malle
M
Kaasik
Allen
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1; D037761:Sirtuins / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000096:biosynthesis; D000099224:p300-CBP-Associated Factor
D000255:Adenosine Triphosphate; D010100:Oxygen; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D056564:Sirtuin 1; D037761:Sirtuins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C501429:Ppargc1a protein, rat; C488368:Sirt1 protein, rat