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...
Parkinson disease is characterized by the accumulation of aggregated ␣-synuclein as the major component of the Lewy bodies. ␣-Synuclein accumulation in turn leads to compensatory effects that may include the up-regulation of autophagy. Another common feature of Parkinson disease (PD) is mitochondrial dysfunction. Here, we provide evidence that the overactivation of autophagy may be a link that connects the intracellular accumulation of ␣-synuclein with mitochondrial dysfunction. We found that the activation of macroautophagy in primary cortical neurons that overexpress mutant A53T ␣-synuclein leads to massive mitochondrial destruction and loss, which is associated with a bioenergetic deficit and neuronal degeneration. No mitochondrial removal or net loss was observed when we suppressed the targeting of mitochondria to autophagosomes by silencing Parkin, overexpressing wild-type Mitofusin 2 and dominant negative Dynamin-related protein 1 or blocking autophagy by silencing autophagy-related genes. The inhibition of targeting mitochondria to autophagosomes or autophagy was also partially protective against mutant A53T ␣-synuclein-induced neuronal cell death. These data suggest that overactivated mitochondrial removal could be one of the contributing factors that leads to the mitochondrial loss observed in PD models. Mitochondrial dysfunction is one of the hallmarks of Parkinson disease (PD).2 The link between mitochondrial dysfunction and PD was made after the discovery of mitochondrial complex I deficiency in the substantia nigra (1). This connection has been supported by the finding that the products of several PDrelated genes show mitochondrial localization under certain conditions, including SNCA, Parkin, PINK1, DJ-1, LRRK2, and HTR2A (2), and that the mitochondrial toxins MPTP, rotenone, and acetogenins can cause PD (3). A variety of mechanisms have been proposed to explain mitochondrial dysfunction. Oxidative stress, mitochondrial DNA deletions, pathological mutations in genes encoding mitochondrial proteins, altered mitochondrial morphology, and the interaction of pathogenic proteins with mitochondria can all lead to mitochondrial dysfunction and neuronal demise (4).In this study, we propose an intriguing possibility whereby mitochondrial dysfunction may arise from the loss of mitochondria because of the overactivation of autophagy. Signs of autophagy have been detected in the brains of PD patients, whereas autophagosomes are rarely detected in normal brain (5-6). Moreover, several studies have also demonstrated that the overexpression of mutant A53T ␣-synuclein in PC12 cells, cultured neurons, and nigrostriatal systems activates autophagy (7-10). Here, we provide evidence that shows that the up-regulation of macroautophagy by mutant A53T ␣-synuclein can augment mitochondrial removal, which results in a net mitochondrial loss, energetic failure, and neuronal cell death. EXPERIMENTAL PROCEDURESNeuronal Cultures-Primary cultures of rat cortical cells were prepared from neonatal Wistar rats. Briefly, cortices w...
Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.
The Parkinson's disease‐associated protein kinase PINK1 and ubiquitin ligase Parkin coordinate the ubiquitination of mitochondrial proteins, which marks mitochondria for degradation. Miro1, an atypical GTPase involved in mitochondrial trafficking, is one of the substrates tagged by Parkin after mitochondrial damage. Here, we demonstrate that a small pool of Parkin interacts with Miro1 before mitochondrial damage occurs. This interaction does not require PINK1, does not involve ubiquitination of Miro1 and also does not disturb Miro1 function. However, following mitochondrial damage and PINK1 accumulation, this initial pool of Parkin becomes activated, leading to the ubiquitination and degradation of Miro1. Knockdown of Miro proteins reduces Parkin translocation to mitochondria and suppresses mitophagic removal of mitochondria. Moreover, we demonstrate that Miro1 EF‐hand domains control Miro1's ubiquitination and Parkin recruitment to damaged mitochondria, and they protect neurons from glutamate‐induced mitophagy. Together, our results suggest that Miro1 functions as a calcium‐sensitive docking site for Parkin on mitochondria.
During early development, neurons undergo complex morphological rearrangements to assemble into neuronal circuits and propagate signals. Rapid growth requires a large quantity of building materials, efficient intracellular transport and also a considerable amount of energy. To produce this energy, the neuron should first generate new mitochondria because the pre-existing mitochondria are unlikely to provide a sufficient acceleration in ATP production. Here, we demonstrate that mitochondrial biogenesis and ATP production are required for axonal growth and neuronal development in cultured rat cortical neurons. We also demonstrate that growth signals activating the CaMKKβ, LKB1-STRAD or TAK1 pathways also co-activate the AMPK-PGC-1α-NRF1 axis leading to the generation of new mitochondria to ensure energy for upcoming growth. In conclusion, our results suggest that neurons are capable of signalling for upcoming energy requirements. Earlier activation of mitochondrial biogenesis through these pathways will accelerate the generation of new mitochondria, thereby ensuring energy-producing capability for when other factors for axonal growth are synthesized.
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