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

Przemyslaw Wareski,Annika Vaarmann,Vinay Choubey,Dzhamilja Safiulina,Joanna Liiv,Malle Kuum,Allen Kaasik

doi:10.1074/jbc.m109.018911

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 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.

Highlights

Tor A), essential for replication, maintenance, and transcription of mitochondrial DNA
We observed that endogenous neuronal PGC-1␣ but not PGC-1␤ could be activated through its repressor domain by suppressing it
PGC-1␣ and PGC-1␤ Control Mitochondrial Density—Overexpression of PGC-1␣ in cortical neurons led to a 13% increase in mitochondrial density in axons, and PGC-1␣ suppression by shRNAs decreased mitochondrial density up to 17% (Fig. 1, A–C)

Summary

Introduction

Tor A), essential for replication, maintenance, and transcription of mitochondrial DNA. PGC-1␣ is important for the expression of nuclear genes encoding respiratory chain subunits and other proteins that are required for proper mitochondrial functions [1,2,3,4]. 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 (p160MBP) 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]. Activation of PGC-1␣ by deacetylation via SIRT1 has been shown to mediate the effects of PGC-1␣ on liver, fat, and muscle metabolism as well as on mitochondrial activity [8]. The aim of the current work was to clarify whether and to what extent the PGC-1 coactivators could regulate mitochondrial capacity in neurons and whether their posttranslational activation could be used to compensate for mitochondrial loss

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Results

Conclusion