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Although more efficient with respect to ATP production, OXPHOS produces additional reactive oxygen species, as compared to glycolysis; thus, endogenous mechanisms to quench free radicals are essential for the maintenance of neuronal health. Melatonin is synthesized in neuronal mitochondria and has a dual role as a free radical scavenger and as an inhibitor of mitochondrial\u2010triggered cell death and proinflammatory pathways. Previously, we showed that loss of endogenous melatonin induced mitochondrial DNA (mtDNA) and cytochrome c (CytC) release triggering pathological inflammation and cell death pathways, respectively. Here we find that in mature neurons, but not undifferentiated neuronal cells, melatonin deficiency altered metabolic reprogramming in aralkylamine <jats:italic>N<\/jats:italic>\u2010acetyltransferase knockout (AANAT\u2010KO) neurons as compared with neurons expressing AANAT. Interestingly, there are no differences in neural progenitors regardless of AANAT status. In addition, AANAT\u2010KO deficiency elevated BAK and BAX levels in AANAT\u2010KO neurons. Further, we found that exogenous melatonin treatment of AANAT\u2010KO cells during differentiation into mature neurons rescued metabolic reprogramming defects and restored normal BAK\/BAX levels. Thus, we demonstrated that the metabolic reprogramming and subsequent consequences of the switch to OXPHOS that normally occurs during neuronal maturation are compromised by melatonin deficiency and rescued by melatonin supplementation.<\/jats:p>","DOI":"10.1111\/jpi.70037","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T15:25:55Z","timestamp":1740151555000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Melatonin Deficits Result in Pathologic Metabolic Reprogramming in Differentiated Neurons"],"prefix":"10.1111","volume":"77","author":[{"given":"Abhishek","family":"Jauhari","sequence":"first","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam C.","family":"Monek","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalikun","family":"Suofu","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia R.","family":"Amygdalos","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanisha","family":"Singh","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei V.","family":"Baranov","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6455-6337","authenticated-orcid":false,"given":"Diane L.","family":"Carlisle","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Friedlander","sequence":"additional","affiliation":[{"name":"Neuroapoptosis Laboratory, Department of Neurological Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.36"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.01.087"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.01.028"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2018.51.11.226"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-200110000-00001"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3208"},{"issue":"1","key":"e_1_2_9_8_1","first-page":"23","article-title":"Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity","volume":"10","author":"Beckhauser T. 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