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Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress

Lookup NU author(s): Professor Tiago OuteiroORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2017.Oxidative stress (OS), mitochondrial dysfunction, and dysregulation of alpha-synuclein (aSyn) homeostasis are key pathogenic factors in Parkinson's disease. Nevertheless, the role of aSyn in mitochondrial physiology remains elusive. Thus, we addressed the impact of aSyn specifically on mitochondrial response to OS in neural cells. We characterize a distinct type of mitochondrial fragmentation, following H 2 O 2 or 6-OHDA-induced OS, defined by spherically-shaped and hyperpolarized mitochondria, termed "mitospheres". Mitosphere formation mechanistically depended on the fission factor Drp1, and was paralleled by reduced mitochondrial fusion. Furthermore, mitospheres were linked to a decrease in mitochondrial activity, and preceded Caspase3 activation. Even though fragmentation of dysfunctional mitochondria is considered to be a prerequisite for mitochondrial degradation, mitospheres were not degraded via Parkin-mediated mitophagy. Importantly, we provide compelling evidence that aSyn prevents mitosphere formation and reduces apoptosis under OS. In contrast, aSyn did not protect against Rotenone, which led to a different, previously described donut-shaped mitochondrial morphology. Our findings reveal a dichotomic role of aSyn in mitochondrial biology, which is linked to distinct types of stress-induced mitochondrial fragmentation. Specifically, aSyn may be part of a cellular defense mechanism preserving neural mitochondrial homeostasis in the presence of increased OS levels, while not protecting against stressors directly affecting mitochondrial function.

Publication metadata

Author(s): Menges S, Minakaki G, Schaefer PM, Meixner H, Prots I, Schlotzer-Schrehardt U, Friedland K, Winner B, Outeiro TF, Winklhofer KF, Von Arnim CAF, Xiang W, Winkler J, Klucken J

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2017

Volume: 7

Online publication date: 22/02/2017

Acceptance date: 17/01/2017

Date deposited: 19/12/2017

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group


DOI: 10.1038/srep42942


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