{"id":232863,"date":"2026-03-09T11:09:41","date_gmt":"2026-03-09T16:09:41","guid":{"rendered":"https:\/\/lifeboat.com\/blog\/2026\/03\/mitochondrial-complex-derived-ros-induces-lysosomal-dysfunction-and-impairs-autophagic-flux-in-human-cells-carrying-the-apoe4-allele"},"modified":"2026-03-09T11:09:41","modified_gmt":"2026-03-09T16:09:41","slug":"mitochondrial-complex-derived-ros-induces-lysosomal-dysfunction-and-impairs-autophagic-flux-in-human-cells-carrying-the-apoe4-allele","status":"publish","type":"post","link":"https:\/\/lifeboat.com\/blog\/2026\/03\/mitochondrial-complex-derived-ros-induces-lysosomal-dysfunction-and-impairs-autophagic-flux-in-human-cells-carrying-the-apoe4-allele","title":{"rendered":"Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele"},"content":{"rendered":"<p><a class=\"aligncenter blog-photo\" href=\"https:\/\/lifeboat.com\/blog.images\/mitochondrial-complex-derived-ros-induces-lysosomal-dysfunction-and-impairs-autophagic-flux-in-human-cells-carrying-the-apoe4-allele.jpg\"><\/a><\/p>\n<p>The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer\u2019s disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 controls, APOE4, and sAD donors to assess mitochondrial bioenergetics, oxidative stress, autophagy, and lysosomal function. APOE4 fibroblasts displayed increased mitochondrial content-associated markers (PGC1\u03b1, mtDNA) accompanied by reduced respiratory capacity, elevated proton leak, and excessive mitochondrial ROS. In parallel, APOE4 fibroblasts showed impaired autophagic flux and reduced LC3-TOMM20 colocalization, indicating defective mitophagy. Lysosomal proteolytic activity, assessed using DQ-BSA, was significantly reduced and remained unresponsive under to starvation, in contrast to the partial recovery observed in sAD cells. Pharmacological targeting of mitochondrial ROS with site-specific inhibitors revealed that complex III-derived ROS is the predominant driver of redox stress in APOE4 fibroblasts, while complex I contributes primarily in sAD. Notably, selective inhibition of complex III-derived ROS with S3QEL restored lysosomal degradation, autophagic flux, and mitochondrial respiration in APOE4 cells. Together, these findings demonstrate that mitochondrial oxidative stress disrupts the mitochondria-lysosome axis in an APOE4-specific manner, revealing early and mechanistically distinct vulnerabilities that may precede neurodegeneration. Our results challenge the notion that APOE4 merely amplifies AD pathology and instead identity site-specific redox signaling as a promising target for allele-informed interventions.<\/p>\n<p><strong class=\"\"> Keywords: <\/strong> APOE4; Autophagy; Human fibroblasts; Lysosome; Mitochondria; Mitochondrial complex III; S3QEL.<\/p>\n<p>Copyright \u00a9 2024. Published by Elsevier B.V.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer\u2019s disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 [\u2026]<\/p>\n","protected":false},"author":662,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11,412,6],"tags":[],"class_list":["post-232863","post","type-post","status-publish","format-standard","hentry","category-biotech-medical","category-genetics","category-robotics-ai"],"_links":{"self":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/232863","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/users\/662"}],"replies":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/comments?post=232863"}],"version-history":[{"count":0,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/232863\/revisions"}],"wp:attachment":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/media?parent=232863"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/categories?post=232863"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/tags?post=232863"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}