title: Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress.
abstract: 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 H2O2or 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.
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Menges
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Minakaki
authors.affiliation: Department of Neurology, Ulm University, 89081 Ulm, Germany.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Schaefer
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Meixner
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, IZKF, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.|Department of Stem Cell Biology, Institute of Human Genetics, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Iryna
authors.initials: I
authors.lastname: Prots
authors.affiliation: Department of Ophthalmology, University Hospital Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.affiliation: Molecular and Clinical Pharmacy, Department of Chemistry and Pharmacy, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Friedland
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, IZKF, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.|Department of Stem Cell Biology, Institute of Human Genetics, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, 37073 Göttingen, Germany.|Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr-University Bochum, 44801 Bochum, Germany.
authors.forename: Konstanze F
authors.initials: KF
authors.lastname: Winklhofer
authors.affiliation: Department of Neurology, Ulm University, 89081 Ulm, Germany.
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
authors.affiliation: Institute of Biochemistry, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Klucken
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D051844:alpha-Synuclein; D012402:Rotenone; D006861:Hydrogen Peroxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D053148:Caspase 3; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C470017:Mfn1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins