BECN1 is involved in the initiation of mitophagy

Choubey, Vinay; Cagalinec, Michal; Liiv, Joanna; Safiulina, Dzhamilja; Hickey, Miriam A.; Kuum, Malle; Liiv, Mailis; Anwar, Tahira; Eskelinen, Eeva‐Liisa; Kaasik, Allen

doi:10.4161/auto.28615

Cited by 97 publications

(61 citation statements)

References 45 publications

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“…Beclin-1, central to the regulation of autophagy, is involved in the formation of autophagosomes via membrane recruitment [23]. LC3 is another important molecule for autophagy as a constituent of the autophagosome membrane [24].…”

Section: Discussionmentioning

confidence: 99%

Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

Zhao

Huang

Chen

et al. 2016

IJMS

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Elevated homocysteine (Hcy) levels have been reported to be involved in neurotoxicity after ischemic stroke. However, the underlying mechanisms remain incompletely understood to date. In the current study, we hypothesized that neuronal autophagy activation may be involved in the toxic effect of Hcy on cortical neurons following cerebral ischemia. Brain cell injury was determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. The level and localization of autophagy were detected by transmission electron microscopy, western blot and immunofluorescence double labeling. The oxidative DNA damage was revealed by immunofluorescence of 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Hcy treatment aggravated neuronal cell death, significantly increased the formation of autophagosomes and the expression of LC3B and Beclin-1 in the brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Immunofluorescence analysis of LC3B and Beclin-1 distribution indicated that their expression occurred mainly in neurons (NeuN-positive) and hardly in astrocytes (GFAP-positive). 8-OHdG expression was also increased in the ischemic cortex of Hcy-treated animals. Conversely, LC3B and Beclin-1 overexpression and autophagosome accumulation caused by Hcy were partially blocked by the autophagy inhibitor 3-methyladenine (3-MA). Hcy administration enhanced neuronal autophagy, which contributes to cell death following cerebral ischemia. The oxidative damage-mediated autophagy may be a molecular mechanism underlying neuronal cell toxicity of elevated Hcy level.

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Section: Discussionmentioning

confidence: 99%

Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

Zhao

Huang

Chen

et al. 2016

IJMS

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“…Plasmids expressing scrambled shRNA or shRNAs against mouse RHOT1 (KM35868N, suppresses efficiently also rat RHOT1), rat RHOT2 (KR44228N) and rat PINK1 (KR55105N) were from SABiosciences and validated earlier (Cagalinec et al , ; Choubey et al , ). Plasmids expressing mitochondrial DsRed2 (632421), mitochondrial CFP (632432) and EGFP (6085‐1) were from Clontech, untagged Miro2 (SC127208) from Origene and mKate2‐mito (FP187) from Evrogen.…”

Section: Methodsmentioning

confidence: 99%

Miro proteins prime mitochondria for Parkin translocation and mitophagy

et al. 2018

Self Cite

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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.

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“…Several studies have suggested a variety of roles for Ambra1 including: (1) interaction with parkin during mitochondrial depolarization, whereupon Ambra1 activates class III PI3K (Van Humbeeck et al, 2011); (2) Ambra1 mediated mitochondrial depolarization and subsequent ubiquitination by parkin; (3) induction of parkin-independent mitophagy; and (4) binding of LC3 to complete autophagophore formation (Strappazzon et al, 2015). Beclin-1 has been shown to bind to both PINK1 and parkin to promote mitophagy and parkin translocation (Choubey et al, 2014). Because of their importance in mitophagy initiation, inducing Ambra1 and Beclin-1 translocation to the mitochondria and/or enhancing their function has the potential to enhance parkin-dependent and -independent mitophagy, thereby enabling the clearance of damaged mitochondria.…”

Section: Therapeuticsmentioning

confidence: 99%

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Scott

Dawson

2017

Experimental Neurology

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Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis. Understanding how aberrancy in these common processes leads to neurodegeneration has provided the field with numerous targets that may be therapeutically relevant to the development of disease-modifying treatments.

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BECN1 is involved in the initiation of mitophagy

Cited by 97 publications

References 45 publications

Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

Miro proteins prime mitochondria for Parkin translocation and mitophagy

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

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