title: Essential regulation of cell bioenergetics in Trypanosoma brucei by the mitochondrial calcium uniporter.
abstract: Mechanisms of regulation of mitochondrial metabolism in trypanosomes are not completely understood. Here we present evidence that the Trypanosoma brucei mitochondrial calcium uniporter (TbMCU) is essential for the regulation of mitochondrial bioenergetics, autophagy and cell death, even in the bloodstream forms that are devoid of a functional respiratory chain and oxidative phosphorylation. Localization studies reveal its co-localization with MitoTracker staining. TbMCU overexpression increases mitochondrial Ca(2+) accumulation in intact and permeabilized trypanosomes, generates excessive mitochondrial reactive oxygen species (ROS) and sensitizes them to apoptotic stimuli. Ablation of TbMCU in RNAi or conditional knockout trypanosomes reduces mitochondrial Ca(2+) uptake without affecting their membrane potential, increases the AMP/ATP ratio, stimulates autophagosome formation and produces marked defects in growth in vitro and infectivity in mice, revealing its essentiality in these parasites. The requirement of TbMCU for proline and pyruvate metabolism in procyclic and bloodstream forms, respectively, reveals its role in regulation of mitochondrial bioenergetics.
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Guozhong
authors.initials: G
authors.lastname: Huang
authors.forename: Anibal E
authors.initials: AE
authors.lastname: Vercesi
authors.forename: Roberto
authors.initials: R
authors.lastname: Docampo
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000166:cytology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000469:parasitology
chemical_list: D015220:Calcium Channels; D015800:Protozoan Proteins; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D002118:Calcium