{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T17:06:06Z","timestamp":1788023166682,"version":"build-2784847793"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"SBI Pharmaceuticals Co., Ltd"},{"DOI":"10.13039\/501100008593","name":"Japan Foundation for Aging and Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Complex I (CI) deficiency in mitochondrial oxidative phosphorylation (OXPHOS) is the most common cause of mitochondrial diseases, and limited evidence-based treatment options exist. Although CI provides the most electrons to OXPHOS, complex II (CII) is another entry point of electrons. Enhancement of this pathway may compensate for a loss of CI; however, the effects of boosting CII activity on CI deficiency are unclear at the animal level. 5-Aminolevulinic acid (5-ALA) is a crucial precursor of heme, which is essential for CII, complex III, complex IV (CIV) and cytochrome c activities. Here, we show that feeding a combination of 5-ALA hydrochloride and sodium ferrous citrate (5-ALA-HCl\u2009+\u2009SFC) increases ATP production and suppresses defective phenotypes in Drosophila with CI deficiency. Knockdown of sicily, a Drosophila homolog of the critical CI assembly protein NDUFAF6, caused CI deficiency, accumulation of lactate and pyruvate and detrimental phenotypes such as abnormal neuromuscular junction development, locomotor dysfunctions and premature death. 5-ALA-HCl\u2009+\u2009SFC feeding increased ATP levels without recovery of CI activity. The activities of CII and CIV were upregulated, and accumulation of lactate and pyruvate was suppressed. 5-ALA-HCl\u2009+\u2009SFC feeding improved neuromuscular junction development and locomotor functions in sicily-knockdown flies. These results suggest that 5-ALA-HCl\u2009+\u2009SFC shifts metabolic programs to cope with CI deficiency.<\/jats:p>\n               <jats:p>Bullet outline 5-Aminolevulinic acid (5-ALA-HCl\u2009+\u2009SFC) increases ATP production in flies with complex I deficiency.5-ALA-HCl\u2009+\u2009SFC increases the activities of complexes II and IV.5-ALA-HCl\u2009+\u2009SFC corrects metabolic abnormalities and suppresses the detrimental phenotypes caused by complex I deficiency.<\/jats:p>","DOI":"10.1093\/hmg\/ddad092","type":"journal-article","created":{"date-parts":[[2023,6,25]],"date-time":"2023-06-25T07:21:57Z","timestamp":1687677717000},"page":"2611-2622","source":"Crossref","is-referenced-by-count":8,"title":["5-Aminolevulinic acid bypasses mitochondrial complex I deficiency and corrects physiological dysfunctions in <i>Drosophila<\/i>"],"prefix":"10.1093","volume":"32","author":[{"given":"Naoko","family":"Nozawa","sequence":"first","affiliation":[{"name":"Tokyo Metropolitan University Department of Biological Sciences, Graduate School of Science, , Tokyo 192-0397 , Japan"},{"name":"SBI Pharmaceuticals Co., Ltd Division of Pharmaceutical Research, , Tokyo 106-6020 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan University Department of Biological Sciences, Graduate School of Science, , Tokyo 192-0397 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Shinno","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan University Department of Biological Sciences, Graduate School of Science, , Tokyo 192-0397 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Saito","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan University Department of Biological Sciences, Graduate School of Science, , Tokyo 192-0397 , Japan"},{"name":"Tokyo Metropolitan University Department of Biological Sciences, School of Science, , Tokyo 192-0397 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Asada","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan University Department of Biological Sciences, Graduate School of Science, , Tokyo 192-0397 , Japan"},{"name":"Tokyo Metropolitan University Department of Biological Sciences, School of Science, , Tokyo 192-0397 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Ishii","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd Division of Pharmaceutical Research, , Tokyo 106-6020 , Japan"},{"name":"Medical- Engineering Collaboration and Innovation Office, National Cancer Center Hospital East , 6-5-1 Kashinoha, Kashiwa, Chiba 277-8577 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiwamu","family":"Takahashi","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd Division of Pharmaceutical Research, , Tokyo 106-6020 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd Division of Pharmaceutical Research, , Tokyo 106-6020 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3956-276X","authenticated-orcid":false,"given":"Kanae","family":"Ando","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan University Department of Biological Sciences, Graduate School of Science, , Tokyo 192-0397 , Japan"},{"name":"Tokyo Metropolitan University Department of Biological Sciences, School of Science, , Tokyo 192-0397 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"2023080814590073400_ref1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s10038-018-0528-6","article-title":"Recent topics: the diagnosis, molecular genesis, and treatment of mitochondrial diseases","volume":"64","author":"Murayama","year":"2019","journal-title":"J. Hum. Genet."},{"key":"2023080814590073400_ref2","doi-asserted-by":"crossref","first-page":"16080","DOI":"10.1038\/nrdp.2016.80","article-title":"Mitochondrial diseases","volume":"2","author":"Gorman","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"2023080814590073400_ref3","doi-asserted-by":"crossref","first-page":"101674","DOI":"10.1016\/j.redox.2020.101674","article-title":"Mitochondrial electron transport chain: oxidative phosphorylation, oxidant production, and methods of measurement","volume":"37","author":"Nolfi-Donegan","year":"2020","journal-title":"Redox Biol."},{"key":"2023080814590073400_ref4","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.tibs.2016.01.001","article-title":"Mitochondrial cristae: where beauty meets functionality","volume":"41","author":"Cogliati","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"2023080814590073400_ref5","doi-asserted-by":"crossref","first-page":"12317","DOI":"10.1038\/ncomms12317","article-title":"Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency","volume":"7","author":"Ehinger","year":"2016","journal-title":"Nat. Commun."},{"key":"2023080814590073400_ref6","doi-asserted-by":"crossref","first-page":"14807","DOI":"10.1073\/pnas.192585799","article-title":"Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging","volume":"99","author":"Atamna","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023080814590073400_ref7","doi-asserted-by":"crossref","first-page":"48410","DOI":"10.1074\/jbc.M108362200","article-title":"Heme deficiency selectively interrupts assembly of mitochondrial complex IV in human fibroblasts: revelance to aging","volume":"276","author":"Atamna","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2023080814590073400_ref8","doi-asserted-by":"crossref","first-page":"10549","DOI":"10.1038\/s41598-019-46772-x","article-title":"Effects of 5-aminolevulinic acid and sodium ferrous citrate on fibroblasts from individuals with mitochondrial diseases","volume":"9","author":"Shimura","year":"2019","journal-title":"Sci. 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Toxicol."},{"key":"2023080814590073400_ref11","doi-asserted-by":"crossref","first-page":"L337","DOI":"10.1152\/ajplung.00482.2005","article-title":"Protoporphyrin IX generation from delta-aminolevulinic acid elicits pulmonary artery relaxation and soluble guanylate cyclase activation","volume":"291","author":"Mingone","year":"2006","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"2023080814590073400_ref12","doi-asserted-by":"crossref","first-page":"eabn8017","DOI":"10.1126\/scisignal.abn8017","article-title":"Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis","volume":"15","author":"Abe","year":"2022","journal-title":"Sci. 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Clin. Exp."},{"key":"2023080814590073400_ref19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ymgme.2006.05.015","article-title":"Lactic acidemia and mitochondrial disease","volume":"89","author":"Robinson","year":"2006","journal-title":"Mol. Genet. Metab."},{"key":"2023080814590073400_ref20","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13023-020-1297-9","article-title":"Molecular basis of Leigh syndrome: a current look","volume":"15","author":"Schubert Baldo","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"2023080814590073400_ref21","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/joim.13054","article-title":"Mitochondrial disease in children","volume":"287","author":"Rahman","year":"2020","journal-title":"J. Intern. 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