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However, despite its value, industrial exploitation of ICA is still limited owing to the lack of cost\u2011effective and selective microbial production processes. Mitochondrial transporters play a pivotal role in controlling the pool sizes and fluxes of tricarboxylic acid (TCA) cycle intermediates by mediating their selective exchange across the inner mitochondrial membrane. Recently, we identified the mitochondrial carriers\n                      <jats:italic>Yl<\/jats:italic>\n                      Yhm2 and\n                      <jats:italic>Yl<\/jats:italic>\n                      Sfc1 in\n                      <jats:italic>Yarrowia lipolytica<\/jats:italic>\n                      as the specific transporters responsible for citric acid (CA) and ICA efflux, respectively, providing for the first time direct control over the selective secretion of these two organic acids. Building on this discovery, a transporter\u2011based metabolic engineering strategy was developed to establish a robust and highly selective ICA\u2011overproducing microbial platform.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Starting from a strain lacking the mitochondrial citrate carrier\n                      <jats:italic>YlYHM2<\/jats:italic>\n                      and overexpressing the mitochondrial ICA exporter\n                      <jats:italic>YlSFC1<\/jats:italic>\n                      , ICA secretion was further enhanced through overexpression of the plasma\u2011membrane exporter\n                      <jats:italic>YlCEX1<\/jats:italic>\n                      . To further increase mitochondrial carbon availability feeding the TCA cycle, we overexpressed transporters capable of mediating net carbon import into mitochondria, including the dicarboxylate carriers\n                      <jats:italic>YlOAC1<\/jats:italic>\n                      and\n                      <jats:italic>YlDIC1<\/jats:italic>\n                      , as well as the pyruvate carrier complex subunits\n                      <jats:italic>YlMPC1<\/jats:italic>\n                      \/\n                      <jats:italic>YlMPC2<\/jats:italic>\n                      , either individually or in combination. Among these,\n                      <jats:italic>YlOAC1<\/jats:italic>\n                      overexpression resulted in the most pronounced improvement, enabling production of 58.4\u2009\u00b1\u20092.4\u00a0g\/L ICA with a molar yield of 0.62\u00a0mol\/mol glucose in shake\u2011flask cultures. Fed\u2011batch bioreactor cultivation of this strain under nitrogen\u2011limited conditions yielded 152.76\u2009\u00b1\u20093.2\u00a0g\/L ICA with a process selectivity of 95% (ICA\/CA\u2009=\u200920), representing the highest titers and selectivity reported to date for a ICA producer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These results clearly demonstrate that precise manipulation of mitochondrial and plasma\u2011membrane transport processes constitutes a powerful and scalable strategy for redirecting carbon flux toward ICA production. This work establishes\n                      <jats:italic>Y. lipolytica<\/jats:italic>\n                      as a robust microbial chassis for industrial ICA manufacturing and highlights selective transport engineering as an effective complementary strategy alongside conventional enzyme centered metabolic engineering approaches, extending and reinforcing previously established roles of mitochondrial carriers in metabolic engineering.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12934-026-03098-4","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:05:49Z","timestamp":1787763949000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial and plasma\u2011membrane transport\u2011based engineering enables industrial\u2011level isocitric acid production in Yarrowia lipolytica"],"prefix":"10.1186","volume":"25","author":[{"given":"Eugenia","family":"Messina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosetta","family":"Ciliberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeniya","family":"Yuzbasheva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Barile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tigran","family":"Yuzbashev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbigniew","family":"Lazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Laptev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinando","family":"Palmieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Palmieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Pisano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5219-4412","authenticated-orcid":false,"given":"Gennaro","family":"Agrimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"issue":"8","key":"3098_CR1","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1134\/S0003683825700292","volume":"61","author":"DA Dementev","year":"2025","unstructured":"Dementev DA, Khabibullin TA, Sineoky SP. 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