title: Inhibition of mitochondrial complex III blocks neuronal differentiation and maintains embryonic stem cell pluripotency.
abstract: The mitochondrion is emerging as a key organelle in stem cell biology, acting as a regulator of stem cell pluripotency and differentiation. In this study we sought to understand the effect of mitochondrial complex III inhibition during neuronal differentiation of mouse embryonic stem cells. When exposed to antimycin A, a specific complex III inhibitor, embryonic stem cells failed to differentiate into dopaminergic neurons, maintaining high Oct4 levels even when subjected to a specific differentiation protocol. Mitochondrial inhibition affected distinct populations of cells present in culture, inducing cell loss in differentiated cells, but not inducing apoptosis in mouse embryonic stem cells. A reduction in overall proliferation rate was observed, corresponding to a slight arrest in S phase. Moreover, antimycin A treatment induced a consistent increase in HIF-1α protein levels. The present work demonstrates that mitochondrial metabolism is critical for neuronal differentiation and emphasizes that modulation of mitochondrial functions through pharmacological approaches can be useful in the context of controlling stem cell maintenance/differentiation.
authors: CNC- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal ; Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.
authors: Sandro L
authors: SL
authors: Pereira
authors: Mário
authors: M
authors: Grãos
authors: Ana Sofia
authors: AS
authors: Rodrigues
authors: Sandra I
authors: SI
authors: Anjo
authors: Rui A
authors: RA
authors: Carvalho
authors: Paulo J
authors: PJ
authors: Oliveira
authors: Ernest
authors: E
authors: Arenas
authors: João
authors: J
authors: Ramalho-Santos
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D000968:Antimycin A; D014450:Electron Transport Complex III