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The arcuate nucleus of the hypothalamus (ARH) plays a critical role in maintaining metabolic homeostasis through its regulation of energy storage and expenditure. Although the importance of mitochondrial bioenergetics to the fitness of ARH neurons has been documented, the functional status of mitochondrial oxidative phosphorylation (OXPHOS) complexes in ARH neurons has not been comprehensively investigated in AD-related settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study investigated the mitochondrial OXPHOS complex enzyme activity in ARH of AD patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We examined ARH mitochondrial OXPHOS complexes and AD-related pathological characteristics in AD patients. We also utilized transcriptome-wide association studies (TWAS) bioinformatics method to predict gene expression changes in ARH mitochondrial-related genes within the AD cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, we identified mitochondrial complex IV dysfunction in tissue homogenate and synaptosomal fractions of postmortem ARH from patients with AD. Further examination determined a reverse correlation between neuronal complex IV dysfunction and ARH amyloid-\u03b2 42. Furthermore, through hypothalamus-specific TWAS analysis we identified multiple AD susceptibility genes that encode key proteins for mitochondrial OXPHOS complex assembly and function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results suggest that ARH neuronal mitochondrial complex IV dysfunction constitutes a phenotypic change in AD that potentially contribute to ARH neuronal stress and dysmetabolism in patients with AD. These findings form a groundwork for future research to understand a hypothalamic mitochondrial pathway of AD pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251352209","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:24:59Z","timestamp":1750638299000},"page":"1545-1556","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Vulnerability of mitochondrial OXPHOS complexes in the arcuate nucleus of the hypothalamus of Alzheimer's disease"],"prefix":"10.1177","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0924-551X","authenticated-orcid":false,"given":"Jing","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai 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