{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T12:28:03Z","timestamp":1775910483476,"version":"3.50.1"},"posted":{"date-parts":[[2024,11,26]]},"group-title":"Microbiology","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,11,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The mitochondrion of the deadliest human malaria parasite,\n                  <jats:italic>Plasmodium falciparum,<\/jats:italic>\n                  is an essential source of cellular acetyl-CoA during the asexual blood-stage of the parasite life cycle. 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 \u03b1-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 antimalarial drug development. We selected the two predicted mitochondrial pyruvate carrier proteins (\n                  <jats:italic>Pf<\/jats:italic>\n                  MPC1 and\n                  <jats:italic>Pf<\/jats:italic>\n                  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\n                  <jats:italic>Pf<\/jats:italic>\n                  MPCs with only minor 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 \u2013 DTC (di\/tricarboxylic acid carrier) and YHM2 (a putative citrate\/\u03b1-ketoglutarate carrier protein) \u2013 only mildly affected asexual blood-stage replication, even in the context of\n                  <jats:italic>Pf<\/jats:italic>\n                  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 blood-stage malaria parasite mitochondrion with imported carbon from two major sources \u2013 glucose and glutamine.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE<\/jats:title>\n                  <jats:p>The mitochondrion of malaria parasites generates key molecules, such as acetyl-CoA, that are required for numerous cellular processes. To support mitochondrial biosynthetic pathways, the parasites must transport carbon sources into this organelle. By studying how the mitochondrion obtains pyruvate, a molecule derived from glucose, we have uncovered redundant carbon transport systems that ensure parasite survival in red blood cells. This metabolic redundancy poses a challenge for drug development, as it enables the parasite to adapt and survive by relying on alternative pathways when one is disrupted.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.11.26.624872","type":"posted-content","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T22:35:12Z","timestamp":1732660512000},"source":"Crossref","is-referenced-by-count":1,"title":["MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM IN\n                  <i>PLASMODIUM FALCIPARUM<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-5471","authenticated-orcid":false,"given":"Krithika","family":"Rajaram","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8208-2817","authenticated-orcid":false,"given":"Gabriel W.","family":"Rangel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin T.","family":"Munro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0957-8699","authenticated-orcid":false,"given":"Sethu C.","family":"Nair","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6173-5882","authenticated-orcid":false,"given":"Manuel","family":"Llin\u00e1s","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9684-1733","authenticated-orcid":false,"given":"Sean 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