{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:55:41Z","timestamp":1790920541491,"version":"4.1.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Genetic mutations causing Complex I (CI) dysfunction lead to the accumulation of NADH in the mitochondrial matrix due to impaired oxidation. An elevated NADH\/NAD\u207a ratio feedback-inhibits key enzymes of the tricarboxylic acid (TCA) cycle, reducing metabolic flux, while concurrent electron transport chain (ETC) blockade exacerbates reactive oxygen species (ROS) generation and oxidative stress. Conventional views propose that the ketogenic diet (KD) bypasses the defective CI to restore downstream ETC electron transfer. However, this perspective harbors an inherent contradiction: CI is the primary entry point for NADH oxidation; bypassing it may sustain some electron flow but fails to consume the accumulated NADH in the matrix, leaving the fate of this critical reducing equivalent inadequately explained. This article proposes the metabolic wisdom of \u201cdredging, not repairing\u201d, positing that KD, through metabolic reprogramming, diverts the accumulated NADH into multiple utilizable pathways. These include intra-matrix conversion and consumption (generating NADPH and ketone bodies), pumping malate from the matrix into the cytosol via the reverse malate-aspartate shuttle (rMAS), and further cytosolic malate utilization (gluconeogenesis, NADPH generation, glycerol-3-phosphate shuttle, etc.). This multi-pathway synergy achieves \u201cdredging\u201drather than \u201crepair\u201d. This paper aims to elucidate how KD, via metabolic reprogramming, alleviates the inhibition of the TCA cycle caused by NADH accumulation and restores its flux, thereby offering new insights into metabolic therapeutic strategies for CI-deficient mitochondrial diseases.<\/jats:p>","DOI":"10.3389\/fped.2026.1939961","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:37:32Z","timestamp":1790919452000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ketogenic diet in treating NADH accumulation caused by complex I dysfunction: the metabolic wisdom of \u201cdredging, not repairing\u201d"],"prefix":"10.3389","volume":"14","author":[{"given":"Xiaoying","family":"Qiao","sequence":"first","affiliation":[{"name":"Department of Neurology, Shenzhen Children\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxiang","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shenzhen Children\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1186\/s13023-021-01927-w","article-title":"Ketogenic diet for mitochondrial disease: a systematic review on efficacy and safety","volume":"16","author":"Zweers","year":"2021","journal-title":"Orphanet J Rare Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1111\/j.1528-1167.2006.00906.x","article-title":"Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects","volume":"48","author":"Kang","year":"2007","journal-title":"Epilepsia"},{"key":"B3","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.bbadis.2016.10.028","article-title":"The addition of ketone bodies alleviates mitochondrial dysfunction by restoring complex I assembly in a MELAS cellular model","volume":"1863","author":"Frey","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1002\/ajmg.1397","article-title":"Respiratory chain complex I deficiency","volume":"106","author":"Triepels","year":"2001","journal-title":"Am J Med Genet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.ymgme.2011.11.188","article-title":"Mitochondrial complex I deficiency of nuclear origin I","volume":"105","author":"Pagniez-Mammeri","year":"2012","journal-title":"Structural Genes Mol Genet Metab"},{"key":"B6","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/s41586-019-1519-2","article-title":"Structure and mechanism of mitochondrial proton-translocating transhydrogenase","volume":"573","author":"Kampjut","year":"2019","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/s41392-020-00326-0","article-title":"NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications","volume":"5","author":"Ju","year":"2020","journal-title":"Signal Transduct Target Ther"},{"key":"B8","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1021\/pr500894v","article-title":"Metabolome and proteome profiling of complex I deficiency induced by rotenone","volume":"14","author":"Gielisch","year":"2015","journal-title":"J Proteome Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.ymgme.2013.12.011","article-title":"In vivo metabolic flux profiling with stable isotopes discriminates sites and quantifies effects of mitochondrial dysfunction in C. 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