Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein -Synuclein
Department of Neurology and Physiology, University of California, San Francisco, California 94158, USA. Journal of Biological Chemistry
(Impact Factor: 4.57).
06/2011; 286(23):20710-26. DOI: 10.1074/jbc.M110.213538
The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than β- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.
Available from: Yujie Yang
- "Recently, several laboratories have published in vitro evidence suggesting localization of α-syn to mitochondria coinciding with increased mitochondrial dysfunction (Cole et al., 2008; Devi et al., 2008), impairing mitochondrial complex I (Devi et al., 2008) or complex IV (Martin et al., 2006) activity, and increasing reactive oxygen species (ROS) production. In cultured cells (Hsu et al., 2000) or transgenic mice (Martin et al., 2006), α-syn leads to the swelling of mitochondria, resulting in distorted membranes or cristae (Stichel et al., 2007) and significant mitochondria fragmentation (Nakamura et al., 2011). A53T α-syn was more potent than wild-type (WT) α-syn with regard to neurotoxicity , but how A53T α-syn leads to neuronal mitochondrial impairment is still unclear. "
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ABSTRACT: Mutations and excessive accumulation of α-synuclein (α-syn) can lead to the degeneration of dopaminergic neurons, indicating a pivotal role of α-syn in the pathogenesis of Parkinson's disease (PD). Although how α-syn contributes to PD is still elusive, mitochondrial impairments have been reported to be implicated in. Mortalin, a molecular chaperone mainly located in mitochondria, has been linked to the pathogenesis of PD in recent studies. Moreover, some proteomics studies indicate that mortalin is associated with PD related proteins, including α-syn. Therefore it is of interest to understand the function of mortalin in the mitochondrial disruption induced by A53T α-syn overexpression. The present study modulated the expression of mortalin and detected the effect of mortalin on the mitochondrial impairments induced by A53T α-syn in SH-SY5Y cells. Our data revealed that A53T α-syn could disrupt mitochondrial dynamics and increase the neuronal susceptibility to neurotoxin rotenone. The expression of mortalin decreased significantly in dopaminergic cells overexpressing A53T α-syn; furthermore, the down-regulation of mortalin could attenuate the disrupted mitochondrial dynamics by reducing α-syn translocation to mitochondria, suggesting that a compensatory mechanism of mortalin might be implicated in the pathogenesis of PD.
Copyright © 2015. Published by Elsevier B.V.
Available from: jcs.biologists.org
- "ion , which could arise from an increase in mitochondrial energy production from fatty acid or amino acid oxidation upon glucose deprivation . Consistent with the proposal that networked mitochondria generate less oxidative stress , mitochondrial fission has been shown to contribute to excessive ROS production in other models ( Yu et al . , 2006 ; Nakamura et al . , 2011 ) . How mitochondrial connectivity affects ROS accumulation is a crucial issue that awaits further investigation . However , we noticed that HDAC6 - , MFN1 - and OPA1 - KO MEFs all showed some degrees of elevated mitochondrial membrane potential ( supplementary material Fig . S3E ) , which has been proposed to increase the electron back"
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ABSTRACT: Fasting and glucose shortage activate a metabolic switch that shifts more energy production to mitochondria. This metabolic adaptation ensures energy supply, but also elevates the risk of mitochondrial oxidative damage. Here we present evidence that metabolically challenged mitochondria undergo active fusion to suppress oxidative stress. In response to glucose starvation, mitofusin 1 (MFN1) becomes associated with the protein deacetylase HDAC6. This interaction leads to MFN1 deacetylation and activation, promoting mitochondrial fusion. Deficiency in HDAC6 or MFN1 prevents mitochondrial fusion induced by glucose deprivation. Unexpectedly, failure to undergo fusion does not acutely affect mitochondrial adaptive energy production; instead, it causes excessive mitochondrial reactive oxygen species and oxidative damage, a defect suppressed by an acetylation-resistant MFN1 mutant. In mice subjected to fasting, skeletal muscle mitochondria undergo dramatic fusion. Remarkably, fasting-induced mitochondrial fusion is abrogated in HDAC6 knockout mice, resulting in extensive mitochondrial degeneration. These findings show that adaptive mitochondrial fusion protects metabolically challenged mitochondria.
Available from: Mathieu Bourdenx
- "Of importance, α-syn seems to induce cell toxicity through its different pathological α-syn species, which include post-translationally modified, mutant, oligomeric and aggregated forms. These can (i) disrupt its typical function in neurotransmission release (Abeliovich et al., 2000; Jenco et al., 1998); (ii) impair mitochondrial dynamics, structure and function (Martin et al., 2006; Nakamura et al., 2011; Stefanovic et al., 2014); and (iii) disrupt ER-Golgi vesicle trafficking (Cooper et al., 2006; Gitler et al., 2008) and mitochondria-associated ER membrane (Mercado et al., 2013; Guardia-Laguarta et al., 2014), which results in ER stress. Further supporting the α-syn species toxicity, CMA inhibition by either PD-linked α-syn mutants or dopamine-modified wild-type α-syn results in an accumulation of α-syn, but also of undegraded CMA-substrates, involved for instance in the regulation of neuronal survival through the degradation of the neuronal survival factor myocyte enhancer factor 2D (MEF2D; Yang et al., 2009). "
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ABSTRACT: Neurodegenerative diseases are (i) characterized by a selective neuronal vulnerability to degeneration in specific brain regions; and (ii) likely to be caused by disease-specific protein misfolding. Parkinson's disease (PD) is characterized by the presence of intraneuronal proteinacious cytoplasmic inclusions, called Lewy Bodies (LB). α-Synuclein, an aggregation prone protein, has been identified as a major protein component of LB and the causative for autosomal dominant PD. Lysosomes are responsible for the clearance of long-lived proteins, such as α-synuclein, and for the removal of old or damaged organelles, such as mitochondria. Interestingly, PD-linked α-synuclein mutants and dopamine-modified wild-type α-synuclein block its own degradation, which result in insufficient clearance, leading to its aggregation and cell toxicity. Moreover, both lysosomes and lysosomal proteases have been found to be involved in the activation of certain cell death pathways. Interestingly, lysosomal alterations are observed in the brains of patients suffering from sporadic PD and also in toxic and genetic rodent models of PD-related neurodegeneration. All these events have unraveled a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. In this review, we emphasize the pathophysiological mechanisms connecting α-synuclein and lysosomal dysfunction in neuronal cell death.
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