scholarly journals Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jae-Hyeon Park ◽  
Jeremy D. Burgess ◽  
Ayman H. Faroqi ◽  
Natasha N. DeMeo ◽  
Fabienne C. Fiesel ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Alpha Synuclein ◽  
Sirtuin 3 ◽  
Dependent Pathway

scholarly journals Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

2018 ◽  
Author(s):  
Jae-Hyeon Park ◽  
Marion Delenclos ◽  
Ayman H. Faroqi ◽  
Natasha N. DeMeo ◽  
Pamela J. McLean
Keyword(s):  
Parkinson Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Lewy Body Disease ◽  
Camp Response Element Binding ◽  
Protective Role ◽  
Alpha Synuclein ◽  
Sirtuin 3

AbstractThe sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that play a broad role in cellular metabolism and aging. Mitochondrial sirtuin 3 (SIRT3) is downregulated in aging and age-associated diseases such as cancer and neuro-degeneration and plays a major role in maintaining mitochondrial function and preventing oxidative stress. Mitochondria dysfunction is central to the pathogenesis of Parkinson disease with mutations in mitochondrial-associated proteins such as PINK1 and parkin causing familial Parkinson disease. Here, we demonstrate that the presence of alpha-synuclein (αsyn) oligomers in mitochondria induce a corresponding decrease in mitochondrial SIRT3 activity and decreased mitochondrial biogenesis. We show that SIRT3 downregulation in the presence of αsyn accumulation is accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB), as well as increased phosphorylation of dynamin-related protein 1 (DRP1) and decreased levels of optic atrophy 1 (OPA1), which is indicative of impaired mitochondrial dynamics. Treatment with the AMPK agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) restores SIRT3 expression and activity and improves mitochondrial function by decreasing αsyn oligomer formation. The accumulation of αsyn oligomers in mitochondria corresponds with SIRT3 down-regulation not only in an experimental cellular model, but also in vivo in a rodent model of Parkinson disease, and importantly, in human post mortem brains with neuropathologically confirmed Lewy body disease (LBD). Taken together our findings suggest that pharmacologically increasing SIRT3 levels will counteract αsyn-induced mitochondrial dysfunction by normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in Parkinson disease-associated pathways and reveals significant mechanistic insight into the interplay of SIRT3 and αsyn.

scholarly journals Epidermal Fatty Acid-Binding Protein 5 (FABP5) Involvement in Alpha-Synuclein-Induced Mitochondrial Injury under Oxidative Stress

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 110
Author(s):  
Yifei Wang ◽  
Yasuharu Shinoda ◽  
An Cheng ◽  
Ichiro Kawahata ◽  
Kohji Fukunaga
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Alpha Synuclein ◽  
Fatty Acid Binding ◽  
Mitochondrial Injury ◽  
Mitochondrial Respiratory Chain Complex ◽  
Acid Binding Protein

The accumulation of α-synuclein (αSyn) has been implicated as a causal factor in the pathogenesis of Parkinson’s disease (PD). There is growing evidence that supports mitochondrial dysfunction as a potential primary cause of dopaminergic neuronal death in PD. Here, we focused on reciprocal interactions between αSyn aggregation and mitochondrial injury induced by oxidative stress. We further investigated whether epidermal fatty acid-binding protein 5 (FABP5) is related to αSyn oligomerization/aggregation and subsequent disturbances in mitochondrial function in neuronal cells. In the presence of rotenone, a mitochondrial respiratory chain complex I inhibitor, co-overexpression of FABP5 with αSyn significantly decreased the viability of Neuro-2A cells compared to that of αSyn alone. Under these conditions, FABP5 co-localized with αSyn in the mitochondria, thereby reducing mitochondrial membrane potential. Furthermore, we confirmed that pharmacological inhibition of FABP5 by its ligand prevented αSyn accumulation in mitochondria, which led to cell death rescue. These results suggested that FABP5 is crucial for mitochondrial dysfunction related to αSyn oligomerization/aggregation in the mitochondria induced by oxidative stress in neurons.

scholarly journals Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD

2011 ◽  
Vol 2011 ◽  
pp. 1-20 ◽  
Author(s):  
A. R. Esteves ◽  
D. M. Arduíno ◽  
D. F. F. Silva ◽  
C. R. Oliveira ◽  
S. M. Cardoso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neuronal Cell ◽  
Alpha Synuclein ◽  
Vital Role ◽  
Microtubule Network ◽  
The Road ◽  
Species Production ◽  
Alpha Synuclein Aggregation

While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers), of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.

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