{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T01:02:22Z","timestamp":1779843742487,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,23]]},"group-title":"Biochemistry","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["R35GM151245"],"award-info":[{"award-number":["R35GM151245"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["F30GM154476"],"award-info":[{"award-number":["F30GM154476"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\u03b1-Lipoic acid (LA) is widely included in \u201cmitochondrial cocktails\u201d recommended to patients with primary mitochondrial disorders, yet its mechanism of action remains unclear. Here, we define the intracellular availability and functional utilization of LA in mammalian cells. We show that LA exists in two functionally distinct cellular pools: a low-abundance free pool and a protein-bound pool generated through mitochondrial fatty acid synthesis (mtFAS). Disruption of the mtFAS pathway abolishes protein lipoylation and impairs oxidative phosphorylation without altering free LA levels. Conversely, supplementation with exogenous LA markedly increases free intracellular LA without restoring protein lipoylation, mitochondrial respiration, or cell proliferation. Instead, the cellular effects of LA supplementation resemble those of the antioxidant N-acetylcysteine. These findings clarify the mechanism of action of a widely used mitochondrial supplement and identify a fundamental disconnect between cellular LA abundance and mitochondrial utilization, challenging the rationale for using LA supplementation to restore mitochondrial function.<\/jats:p>","DOI":"10.64898\/2026.05.22.727209","type":"posted-content","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T11:10:20Z","timestamp":1779534620000},"source":"Crossref","is-referenced-by-count":0,"title":["Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization"],"prefix":"10.64898","author":[{"given":"Pieter R.","family":"Norden","sequence":"first","affiliation":[{"name":"Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riley J.","family":"Wedan","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI"},{"name":"The Van Andel Institute Graduate School, Grand Rapids, MI"},{"name":"College of Human Medicine, Michigan State University, Grand Rapids, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail E.","family":"Ellis","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine L.","family":"Hart","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan R.","family":"Gendjar","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan D.","family":"Sheldon","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Nowinski","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052617053906000_2026.05.22.727209v1.1","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.bbadis.2016.11.010","article-title":"Mitochondrial dysfunction and oxidative stress in metabolic disorders - A step towards mitochondria based therapeutic strategies","volume":"1863","year":"2017","journal-title":"Biochim. 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