{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:42:16Z","timestamp":1790800936325,"version":"4.1.0"},"reference-count":117,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T00:00:00Z","timestamp":1718150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01HL144943"],"award-info":[{"award-number":["R01HL144943"]}]},{"name":"National Institutes of Health","award":["RO1HL157583"],"award-info":[{"award-number":["RO1HL157583"]}]},{"name":"National Institutes of Health","award":["23TPA1077648"],"award-info":[{"award-number":["23TPA1077648"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association Transformational Project Award","doi-asserted-by":"publisher","award":["R01HL144943"],"award-info":[{"award-number":["R01HL144943"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association Transformational Project Award","doi-asserted-by":"publisher","award":["RO1HL157583"],"award-info":[{"award-number":["RO1HL157583"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association Transformational Project Award","doi-asserted-by":"publisher","award":["23TPA1077648"],"award-info":[{"award-number":["23TPA1077648"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>There is a \u201cpopular\u201d belief that a fat-free diet is beneficial, supported by the scientific dogma indicating that high levels of fatty acids promote many pathological metabolic, cardiovascular, and neurodegenerative conditions. This dogma pressured scientists not to recognize the essential role of fatty acids in cellular metabolism and focus on the detrimental effects of fatty acids. In this work, we critically review several decades of studies and recent publications supporting the critical role of mitochondrial fatty acid metabolism in cellular homeostasis and many pathological conditions. Fatty acids are the primary fuel source and essential cell membrane building blocks from the origin of life. The essential cell membranes phospholipids were evolutionarily preserved from the earlier bacteria in human subjects. In the past century, the discovery of fatty acid metabolism was superseded by the epidemic growth of metabolic conditions and cardiovascular diseases. The association of fatty acids and pathological conditions is not due to their \u201charmful\u201d effects but rather the result of impaired fatty acid metabolism and abnormal lifestyle. Mitochondrial dysfunction is linked to impaired metabolism and drives multiple pathological conditions. Despite metabolic flexibility, the loss of mitochondrial fatty acid oxidation cannot be fully compensated for by other sources of mitochondrial substrates, such as carbohydrates and amino acids, resulting in a pathogenic accumulation of long-chain fatty acids and a deficiency of medium-chain fatty acids. Despite popular belief, mitochondrial fatty acid oxidation is essential not only for energy-demanding organs such as the heart, skeletal muscle, and kidneys but also for metabolically \u201cinactive\u201d organs such as endothelial and epithelial cells. Recent studies indicate that the accumulation of long-chain fatty acids in specific organs and tissues support the impaired fatty acid oxidation in cell- and tissue-specific fashion. This work, therefore, provides a basis to challenge these established dogmas and articulate the need for a paradigm shift from the \u201cpathogenic\u201d role of fatty acids to the critical role of fatty acid oxidation. This is important to define the causative role of impaired mitochondrial fatty acid oxidation in specific pathological conditions and develop novel therapeutic approaches targeting mitochondrial fatty acid metabolism.<\/jats:p>","DOI":"10.3390\/ijms25126498","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T03:52:53Z","timestamp":1718337173000},"page":"6498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Critical Role of Mitochondrial Fatty Acid Metabolism in Normal Cell Function and Pathological Conditions"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2976-6184","authenticated-orcid":false,"given":"Sergey","family":"Dikalov","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB 554, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Panov","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB 554, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dikalova","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB 554, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.reprotox.2016.10.001","article-title":"Metabolism disrupting chemicals and metabolic disorders","volume":"68","author":"Heindel","year":"2017","journal-title":"Reprod. 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