BCKDH: The Missing Link in Apicomplexan Mitochondrial Metabolism Is Required for Full Virulence of and

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The mitochondrial tricarboxylic acid (TCA) cycle is one of the core metabolic pathways of eukaryotic cells, which contributes to cellular energy generation and provision of essential intermediates for macromolecule synthesis. Apicomplexan parasites possess the complete sets of genes coding for the TCA cycle. However, they lack a key mitochondrial enzyme complex that is normally required for production of acetyl-CoA from pyruvate, allowing further oxidation of glycolytic intermediates in the TCA cycle. This study unequivocally resolves how acetyl-CoA is generated in the mitochondrion using a combination of genetic, biochemical and metabolomic approaches. Specifically, we show that T. gondii and P. bergei utilize a second mitochondrial dehydrogenase complex, BCKDH, that is normally involved in branched amino acid catabolism, to convert pyruvate to acetyl-CoA and further catabolize glucose in the TCA cycle. In T. gondii, loss of BCKDH leads to global defects in glucose metabolism, increased gluconeogenesis and a marked attenuation of growth in host cells and virulence in animals. In P. bergei, loss of BCKDH leads to a defect in parasite proliferation in mature red blood cells, although the mutant retains the capacity to proliferate within 'immature' reticulocytes, highlighting the role of host metabolism/physiology on the development of Plasmodium asexual stages.

Vyšlo v časopise: BCKDH: The Missing Link in Apicomplexan Mitochondrial Metabolism Is Required for Full Virulence of and. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004263
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004263

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