Summary of project PR002196
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002196. The data can be accessed directly via it's Project DOI: 10.21228/M8RV6M This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002196 |
| Project DOI: | doi: 10.21228/M8RV6M |
| Project Title: | Multiple, redundant carboxylic acid transporters support mitochondrial metabolism in Plasmodium falciparum |
| Project Summary: | The mitochondrion of the deadliest human malaria parasite, Plasmodium falciparum, is an essential source of cellular acetyl-CoA during the asexual blood-stage of the parasite life cycle. Indeed, blocking mitochondrial acetyl-CoA synthesis leads to a hypoacetylated proteome and parasite death. We previously determined that mitochondrial acetyl-CoA is primarily synthesized from glucose-derived pyruvate by α-ketoacid dehydrogenases. Here, we asked if inhibiting the import of glycolytic pyruvate across the mitochondrial inner membrane would affect acetyl-CoA production and, thus, could be a potential target for novel antimalarial drug development. We selected the two predicted mitochondrial pyruvate carrier proteins (MPC1 and MPC2) for genetic knockout and isotopic metabolite tracing via HPLC-MS metabolomic analysis. Surprisingly, we observed that asexual blood-stage parasites could survive the loss of either or both proteins with only minor asexual blood-stage growth defects, despite a substantial reduction in the amount of glucose-derived isotopic labelling into acetyl-CoA. Furthermore, genetic deletion of two additional mitochondrial carboxylic acid transporters – DTC (di/tricarboxylic acid carrier) and YHM2 (a putative citrate/α-ketoglutarate carrier protein) – only mildly affected asexual blood-stage replication, even in the context of MPC-deficiency. Although we observed no added impact on the incorporation of glucose carbon into acetyl-CoA in these quadruple knockout mutants, we noted a large decrease in glutamine-derived label in tricarboxylic acid cycle metabolites, suggesting that DTC and YHM2 both import glutamine derivatives into the mitochondrion. Altogether, our results expose redundant routes used to fuel the mitochondria of blood-stage malaria parasites with imported carbon from two major carbon sources – glucose and glutamine. |
| Institute: | Pennsylvania State University |
| Department: | Biochemistry and Molecular Biology |
| Laboratory: | Manuel Llinás |
| Last Name: | Manuel |
| First Name: | Llinás |
| Address: | 491 Pollock Road, Millennium Science Complex, W126 |
| Email: | manuel@psu.edu |
| Phone: | 814-867-3444 |
Summary of all studies in project PR002196
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003562 | Multiple, redundant carboxylic acid transporters support mitochondrial metabolism in Plasmodium falciparum | Plasmodium falciparum | Pennsylvania State University | MS | 2024-11-20 | 1 | 164 | Uploaded data (5.7G)* |
