Essential regulation of cell bioenergetics in Trypanosoma brucei by the mitochondrial calcium uniporter

Author(s)

Huang, Guozhong ^{[1, 2]} ; Vercesi, Anibal E. ^[3] ; Docampo, Roberto ^{[1, 2]}

Affiliation

^[1] Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 - USA

^[2] Univ Georgia, Dept Cellular Biol, Athens, GA 30602 - USA

^[3] Univ Estadual Campinas, Dept Clin Pathol, BR-13083887 Campinas, SP - Brazil

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 4, DEC 2013.
• Web of Science Citations: 100

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 Ca2+ 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 Ca2+ 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. (AU)

• FAPESP's process: 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants