Beclin 1-independent pathway of damage-induced mitophagy and autophagic stress: implications for neurodegeneration and cell death.
Growing evidence supports an active role for dysregulated macroautophagy (autophagic stress) in neuronal cell death and neurodegeneration. Alterations in mitochondrial function and dynamics are also strongly implicated in neurodegenerative diseases. Interestingly, whereas the core autophagy machinery is evolutionarily conserved and shared among constitutive and induced or selective autophagy, recent studies implicate distinct mechanisms regulating mitochondrial autophagy (mitophagy) in response to general autophagic stimuli. Little is known about pathways regulating selective, damage-induced mitophagy. We found that the parkinsonian neurotoxin MPP(+) induces autophagy and mitochondrial degradation that is inhibited by siRNA knockdown of autophagy proteins Atg5, Atg7 and Atg8, but occurs independently of Beclin 1, a component of the class III (PIK3C3/Vps34) phosphoinositide 3-kinase (PI3K) complex. Instead, MPP(+)-induced mitophagy is dependent upon MAPK signaling. Interestingly, all treatments that inhibited autophagy also conferred protection from MPP(+)-induced cell death. A prior human tissue study further supports a role for ERK/MAPK-regulated autophagy in Parkinson's and Lewy body diseases. As competition for limiting amounts of Beclin 1 may serve to prevent harmful overactivation of autophagy, understanding mechanisms that bypass or complement a requirement for PI3K-Beclin 1 activity could lead to strategies to modulate autophagic stress in injured or degenerating neurons.
Chu
Charleen T
CT
Department of Pathology, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. ctc4@pitt.edu
Zhu
Jianhui
J
Dagda
Ruben
R
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008565:Membrane Proteins; D008928:Mitochondria / Q000187:drug effects*; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011506:Proteins; D034741:RNA, Small Interfering / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D015655:1-Methyl-4-phenylpyridinium; D020123:Sirolimus