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Biochem J. 2017 Jun 27;474(14):2315-2332. doi: 10.1042/BCJ20170084.

Heme A synthesis and CcO activity are essential for Trypanosoma cruzi infectivity and replication.

Author information

1
Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario UNR, Suipacha 531, S2002LRK Rosario, Argentina.
2
Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario UNR, Suipacha 531, S2002LRK Rosario, Argentina cricco@ibr-conicet.gov.ar.
3
Área Biofísica, Departamento de Química Biológica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario UNR, Suipacha 531, S2002LRK Rosario, Argentina.

Abstract

Trypanosoma cruzi, the causative agent of Chagas disease, presents a complex life cycle and adapts its metabolism to nutrients' availability. Although T. cruzi is an aerobic organism, it does not produce heme. This cofactor is acquired from the host and is distributed and inserted into different heme-proteins such as respiratory complexes in the parasite's mitochondrion. It has been proposed that T. cruzi's energy metabolism relies on a branched respiratory chain with a cytochrome c oxidase-type aa3 (CcO) as the main terminal oxidase. Heme A, the cofactor for all eukaryotic CcO, is synthesized via two sequential enzymatic reactions catalyzed by heme O synthase (HOS) and heme A synthase (HAS). Previously, TcCox10 and TcCox15 (Trypanosoma cruzi Cox10 and Cox15 proteins) were identified in T. cruzi They presented HOS and HAS activity, respectively, when they were expressed in yeast. Here, we present the first characterization of TcCox15 in T. cruzi, confirming its role as HAS. It was differentially detected in the different T. cruzi stages, being more abundant in the replicative forms. This regulation could reflect the necessity of more heme A synthesis, and therefore more CcO activity at the replicative stages. Overexpression of a non-functional mutant caused a reduction in heme A content. Moreover, our results clearly showed that this hindrance in the heme A synthesis provoked a reduction on CcO activity and, in consequence, an impairment on T. cruzi survival, proliferation and infectivity. This evidence supports that T. cruzi depends on the respiratory chain activity along its life cycle, being CcO an essential terminal oxidase.

KEYWORDS:

Chagas disease; complex IV; heme A; heme A synthase; trypanosomes

PMID:
28588043
DOI:
10.1042/BCJ20170084
[Indexed for MEDLINE]

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