{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:56:34Z","timestamp":1785412594195,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,15]]},"group-title":"Genetics","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R21TR005163"],"award-info":[{"award-number":["R21TR005163"]}]},{"id":[{"id":"https:\/\/ror.org\/00zc03z98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Propionic acidemia (PA) is an inborn error of metabolism caused by propionyl-CoA carboxylase (PCC) deficiency due to mutations in either\n                  <jats:italic>PCCA<\/jats:italic>\n                  or\n                  <jats:italic>PCCB<\/jats:italic>\n                  . Without proper management, the disease is associated with high mortality. Even with dietary restriction, patients often develop complications later in life, and the underlying pathological mechanisms remain poorly understood. The liver is the primary organ responsible for propionyl-CoA metabolism, yet the metabolic alterations induced by PCC deficiency in the liver have not been systematically investigated. In this study, we used a hepatocyte model of PA\u2014\n                  <jats:italic>\n                    PCCA\n                    <jats:sup>null<\/jats:sup>\n                    -\n                  <\/jats:italic>\n                  HepG2 cells\u2014to comprehensively examine metabolic alterations using stable isotope\u2013based metabolic flux analysis. The\n                  <jats:italic>PCCA<\/jats:italic>\n                  knockout recapitulated key metabolic features of PA in HepG2 cells. Furthermore,\n                  <jats:italic>PCCA<\/jats:italic>\n                  deficiency reduced mitochondrial fatty acid oxidation while increasing glucose oxidation through pyruvate dehydrogenase. In contrast, pyruvate anaplerosis via pyruvate carboxylase was markedly reduced in\n                  <jats:italic>PCCA<\/jats:italic>\n                  knockout cells. This reduction in anaplerotic flux impaired the capacity for gluconeogenesis and lipid synthesis, consistent with observations from\n                  <jats:italic>in vivo<\/jats:italic>\n                  studies in\n                  <jats:italic>Pcca\u207b\/\u207b<\/jats:italic>\n                  (A138T) mice. Additionally, branched-chain keto acid catabolism was reduced in\n                  <jats:italic>PCCA<\/jats:italic>\n                  knockout HepG2 cells. Threonine showed minimal metabolic contribution in this model, further supporting the role of propionate as a major source of propionyl-CoA production. Collectively, these findings highlight the metabolic vulnerabilities associated with PCC deficiency and underscore the increased risk of prolonged fasting in patients with PA, particularly those with severe disease.\n                <\/jats:p>","DOI":"10.64898\/2026.04.13.718201","type":"posted-content","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T04:30:14Z","timestamp":1776313814000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of Propionyl-CoA Carboxylase Reprograms Hepatic Metabolism by Suppressing Mitochondrial Pyruvate Carboxylation and Fatty Acid Oxidation"],"prefix":"10.64898","author":[{"given":"Fang","family":"Lu","sequence":"first","affiliation":[{"name":"Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chorlada","family":"Paiboonrungruang","sequence":"additional","affiliation":[{"name":"Coriell Institute for Medical Research, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"He","sequence":"additional","affiliation":[{"name":"Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Xiong","sequence":"additional","affiliation":[{"name":"Coriell Institute for Medical Research, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingchuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takhar","family":"Kasumov","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Coriell Institute for Medical Research, Camden, NJ 08103, USA"},{"name":"Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ 08103, USA"},{"name":"MD Anderson Cancer Center at Cooper, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA"},{"name":"Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Duke University Medical Center, Durham, NC 27701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041804250617000_2026.04.13.718201v1.1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-014-0130-8"},{"key":"2026041804250617000_2026.04.13.718201v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12665"},{"key":"2026041804250617000_2026.04.13.718201v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2022.100936"},{"key":"2026041804250617000_2026.04.13.718201v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12129"},{"key":"2026041804250617000_2026.04.13.718201v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12128"},{"key":"2026041804250617000_2026.04.13.718201v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/JIMD.12478"},{"key":"2026041804250617000_2026.04.13.718201v1.7","doi-asserted-by":"publisher","DOI":"10.3390\/metabo13040563"},{"key":"2026041804250617000_2026.04.13.718201v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108501"},{"key":"2026041804250617000_2026.04.13.718201v1.9","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/7653716"},{"key":"2026041804250617000_2026.04.13.718201v1.10","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2020.617451"},{"key":"2026041804250617000_2026.04.13.718201v1.11","doi-asserted-by":"publisher","DOI":"10.1002\/jmd2.12234"},{"key":"2026041804250617000_2026.04.13.718201v1.12","unstructured":"Shchelochkov, O.A. , Carrillo, N. , and Venditti, C. 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