{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:49:34Z","timestamp":1782103774309,"version":"3.54.5"},"reference-count":137,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    The longevity and functional maintenance of Leydig cells (LCs) depend on an extracellular vesicle (EV)\u2013mediated mitochondrial outsourcing system. In contrast to the conventional focus on intracellular quality control, LCs orchestrate a bidirectional EV transfer network with testicular macrophages: they export EVs containing defective mitochondria to CD206\n                    <jats:sup>+<\/jats:sup>\n                    macrophages for clearance (the scavenger pathway), while importing EVs with healthy mitochondria from MHCII\n                    <jats:sup>+<\/jats:sup>\n                    macrophages (the donor pathway). During aging, this network undergoes three-dimensional disruption\u2014donor-side collapse characterized by diminished PGC-1\u03b1, a shift toward Drp1 predominance over Mfn2, and NAD\n                    <jats:sup>+<\/jats:sup>\n                    depletion; scavenger-side obstruction reflected in reduced TREM2 and impaired phagosome-lysosome fusion; and communication uncoupling driven by decay of the VCAM1\/ITG\u03b21 axis. These coordinated failures precipitate a mitochondrial quality crisis, steroidogenic enzyme dysfunction, and progressive loss of LCs, thereby initiating and driving late-onset hypogonadism (LOH). Individual variability in EV network efficiency dictates LOH susceptibility, and the point of network decompensation marks the transition from a compensated state to clinical disease. In-depth dissection of this network and its dysregulation may yield novel strategies for early diagnosis (INSL3, EV-miRNA signatures, mtDNA mutation burden) and targeted therapy (MSC-EVs, NAD\n                    <jats:sup>+<\/jats:sup>\n                    precursors, TREM2 activation).\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1866059","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:33:35Z","timestamp":1782102815000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The EV-mitochondrial outsourcing network as a therapeutic target for age-related testosterone deficiency: from network collapse to clinical intervention"],"prefix":"10.3389","volume":"17","author":[{"given":"Lu","family":"Zhou","sequence":"first","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingzhao","family":"Tian","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiteng","family":"Wang","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiucheng","family":"Lan","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijing","family":"Wang","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjun","family":"Li","sequence":"additional","affiliation":[{"name":"Chengdu Fifth People\u2019s Hospital","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Dong","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujun","family":"Yu","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yang","sequence":"additional","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, 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