{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:05:39Z","timestamp":1790759139803,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003489","name":"Cultivation Project of Tuoxin Team","doi-asserted-by":"publisher","award":["2025TXTD15"],"award-info":[{"award-number":["2025TXTD15"]}],"id":[{"id":"10.13039\/501100003489","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Mitochondria\u2013lysosome coupling and mitophagy are fundamental to mitochondrial homeostasis, yet the determinants governing this process remain incompletely defined. This study distinguished the regulatory modes of TBC1D15 and established its functional role as a downstream effector in mitochondria-linked autophagy. Methods: PC-12 and HeLa cells were treated with CCCP, gradient-concentrated AuNPs, and CQ, combined with siRNA-mediated PINK1 knockdown. Whole-cell, mitochondrial and lysosomal fractions were analyzed by immunoblotting. Results: Inter-organelle translocation of TBC1D15, rather than its total abundance, serves as the critical switch for mitochondria\u2013lysosome homeostasis. CCCP induced a time-dependent biphasic change in TBC1D15 that persisted upon PINK1 knockdown, indicating regulation is not strictly PINK1-dependent. High-dose AuNPs trapped TBC1D15 on mitochondria and blocked lysosomal delivery via a PINK1-independent route. AuNPs exhibited biphasic concentration-dependent effects: low concentrations moderately upregulated TBC1D15, promoting adaptive organelle contacts, while millimolar concentrations caused pathological tethering. Subcellular fractionation and CQ intervention confirmed that defective lysosomal delivery underlies mitochondrial TBC1D15 accumulation upon AuNP challenge. Conclusions: This work establishes two distinct regulatory axes converging on TBC1D15. High-dose AuNPs can serve as a specific pharmacological blocker of TBC1D15 trafficking, offering therapeutic avenues for disorders characterized by impaired mitophagy.<\/jats:p>","DOI":"10.3390\/cells15191781","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:17:27Z","timestamp":1790756247000},"page":"1781","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Disrupting Mitochondrial Homeostasis via TBC1D15 Protein"],"prefix":"10.3390","volume":"15","author":[{"given":"Pengfei","family":"Qiang","sequence":"first","affiliation":[{"name":"College of Biological Engineering, Henan University of Technology, Zhengzhou 450000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"College of Biological Engineering, Henan University of Technology, Zhengzhou 450000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Shuang","family":"Liang","sequence":"additional","affiliation":[{"name":"College of Biological Engineering, Henan University of Technology, Zhengzhou 450000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Miaomiao","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Biological Engineering, Henan University of Technology, Zhengzhou 450000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Shuoye","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Biological Engineering, Henan University of Technology, Zhengzhou 450000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5073-3569","authenticated-orcid":false,"given":"Xiwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Biological Engineering, Henan University of Technology, Zhengzhou 450000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41586-021-03510-6","article-title":"Distinct fission signatures predict mitochondrial degradation or biogenesis","volume":"593","author":"Kleele","year":"2021","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"108698","DOI":"10.1016\/j.abb.2020.108698","article-title":"Mitochondrial dysfunction in the development and progression of neurodegenerative diseases","volume":"702","author":"Johnson","year":"2021","journal-title":"Arch. 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