PGC-1α and PGC-1Β Regulate Mitochondrial Density in Neurons

Abstract

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 ␥ coactivator-1␣ (PGC-1␣) 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-1␣ and PGC-1␤ control mitochondrial density also in neurons and if these coactivators could be up-regulated by deacetylation. The results demonstrate that PGC-1␣ and PGC-1␤ 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-1␣ but not PGC-1␤ 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-1␣ in neurons and increases mitochondrial density. These effects were mediated exclusively via PGC-1␣, since overexpression of SIRT1 or suppression of GCN5 was ineffective where PGC-1␣ was suppressed by short hairpin RNA. Moreover, the results demonstrate that overexpression of PGC-1␤ or PGC-1␣ or activation of the latter by SIRT1 protected neurons from mutant ␣-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.Previous studies have shown that the PGC-1 family of coactivators, particularly PGC-1␣, are potent stimulators of mitochondrial respiration and gene transcription in liver, heart, and skeletal muscle. It has been shown that PGC-1␣ acts by activating the nuclear respiratory factors NRF1 and NRF2 that in turn regulate expression of Tfam (mitochondrial transcription factor A), essential for replication, maintenance, and transcription of mitochondrial DNA. PGC-1␣ is also important for the expression of nuclear genes encoding respiratory chain subunits and other proteins that are required for proper mitochondrial functions (1-4).Apart from gene expression, the activity of PGC-1␣ is influenced by posttranscriptional regulation by means of protein phosphorylation, acetylation, and methylation. PGC-1␣ is known to be regulated by p38 mitogen-activated protein kinase through the inhibition of the p160 Myb-binding protein (p160 MBP ) 2 in brown fat cells and myotubes (5, 6). AMPK (AMP-activated protein kinase) phosphorylation of PGC-1␣ initiates many of the important gene-regulatory functions of AMPK in skeletal muscle (7). Acetylation status of PGC-1␣ is, on the other hand, regulated by t...

Mitochondrial biogenesis is required for axonal growth

“…Of note, PGC-1α also increases the ATP/ADP ratio in axonal endings. Increased mitochondrial density specifically in the periphery of PGC-1α-overexpressing neurons cannot be explained by simple redistribution of mitochondria from the cell body to the periphery because PGC-1α overexpression does not decrease mitochondrial density in the neuronal body (Wareski et al, 2009). Instead, this could be explained by an increased mitochondrial fusion rate helping to distribute mitochondria more homogenously throughout the PGC-1α-overexpressing cell.…”

“…We have previously demonstrated that PGC-1α overexpression increases mitofusin 2 (Mfn2) promoter activity (Wareski et al, 2009). MFN2 is known to be directly regulated by PGC-1α, independently of NRF2 (Wareski et al, 2009).…”

“…MFN2 is known to be directly regulated by PGC-1α, independently of NRF2 (Wareski et al, 2009). To determine the functional outcome of increased MFN2, we quantified mitochondrial fusion events using the mitochondria-targeted photoconvertible KikGR1 protein.…”

“…We have previously demonstrated that PGC-1α and PGC-1β (PPARGC1B) levels and activity control mitochondrial number and energy production both in axons and the cell body (Wareski et al, 2009). Recent findings indicate that PGC-1α also controls mitochondrial density in dendrites (Cheng et al, 2012).…”

“…Plasmids expressing scrambled shRNA or shRNA targeted against rat PGC-1α were obtained from SABiosciences and were previously validated by us (Wareski et al, 2009). Plasmids expressing mitochondrial DsRed2 (mitoDsRed, 632421) and eGFP (6085-1) were from Clontech.…”