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Maternal supraphysiological hypercholesterolemia (MSPH) is associated with increased maternal levels of total cholesterol (TC) and low\u2010density lipoprotein (LDL). This condition has been linked to negative consequences on the fetoplacental vasculature, including increased atherosclerosis development in the fetal aorta and later in children and adolescents. This study aims to determine whether the high cholesterol levels associated with MSPH affect lysosomal and mitochondrial functions in the syncytiotrophoblast (STB), considering the increased free cholesterol levels previously reported in primary human trophoblast (PHT) cells from MSPH pregnancies. Total cholesterol levels were measured in placental tissues and BeWo cells. Lysosomal mass, size, and activity, as well as mitochondrial mass, function, and morphology, were assessed in BeWo cells and placentas. Our results revealed that placental tissues from MSPH pregnancies and BeWo cells treated with oxidized (ox\u2010LDL) exhibited increased free cholesterol levels and higher expression of cholesterol transport proteins. Treatment of BeWo cells with ox\u2010LDL also led to an increase in lysosomal mass and size, accompanied by a decrease in lysosomal activity. Conversely, ox\u2010LDL treatment induced mitochondrial fragmentation in BeWo cells, together with reduced ATP production and diminished mitochondrial membrane potential. Similar alterations in lysosomes and mitochondria were observed in the placenta of patients with a history of MSPH. MSPH\u2010related high cholesterol levels induced by ox\u2010LDL impair lysosomal and mitochondrial functions in the STB, potentially contributing to cellular dysfunction observed in MSPH. This study highlights the importance of understanding the underlying mechanisms of MSPH to improve maternal and fetal health outcomes.<\/jats:p>","DOI":"10.1002\/jcp.70165","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T09:30:48Z","timestamp":1775467848000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Impact of Maternal Supraphysiological Hypercholesterolemia on Lysosomal and Mitochondrial Function in Placental Trophoblast Cells"],"prefix":"10.1002","volume":"241","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7990-2079","authenticated-orcid":false,"given":"Mar\u00eda Jos\u00e9","family":"Ya\u00f1ez","sequence":"first","affiliation":[{"name":"Facultad de Ciencias Universidad San Sebasti\u00e1n Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabi\u00e1n","family":"Campos","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias 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