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The mitochondrial complex I inhibitor, rotenone (ROT), reproduces \u03b1-synuclein (\u03b1-syn) aggregation seen in Parkinson\u2019s disease (PD). In this present study, we examined the neuroprotective effects of the secretome from neural-induced human adipose tissue-derived stem cells (NI-ADSC-SM) during ROT toxicity in SH-SY5Y cells. Exposure to ROT significantly impaired the mitophagy by increased LRRK2, mitochondrial fission, and endoplasmic reticulum (ER) stress (ERS). ROT also increased the levels of calcium (Ca2+), VDAC, and GRP75, and decreased phosphorylated (p)-IP3R Ser1756\/total (t)-IP3R1. However, NI-ADSC-SM treatment decreased Ca2+ levels along with LRRK2, insoluble ubiquitin, mitochondrial fission by halting p-DRP1 Ser616, ERS by reducing p-PERK Thr981, p-\/t-IRE1\u03b1, p-SAPK, ATF4, and CHOP. In addition, NI-ADSC-SM restored the mitophagy, mitochondrial fusion, and tethering to the ER. These data suggest that NI-ADSC-SM decreases ROT-induced dysfunction in mitochondria and the ER, which subsequently stabilized tethering in mitochondria-associated membranes in SH-SY5Y cells.<\/jats:p>","DOI":"10.3390\/ijms24065622","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T03:14:35Z","timestamp":1678936475000},"page":"5622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Neuroprotective Effects of the Neural-Induced Adipose-Derived Stem Cell Secretome against Rotenone-Induced Mitochondrial and Endoplasmic Reticulum Dysfunction"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8831-4375","authenticated-orcid":false,"given":"Mahesh","family":"Ramalingam","sequence":"first","affiliation":[{"name":"Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8673-7887","authenticated-orcid":false,"given":"Sujeong","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsu","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4953-7226","authenticated-orcid":false,"given":"Boeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Gwangju Alzheimer\u2019s Disease and Related Dementias (GARD) Cohort Center, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1331-4039","authenticated-orcid":false,"given":"Hyong-Ho","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju 61469, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eungpil","family":"Kim","sequence":"additional","affiliation":[{"name":"Biopharmaceutical Research Center, Jeonnam Bioindustry Foundation, Hwasun 58141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6921-6625","authenticated-orcid":false,"given":"Han-Seong","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tips.2009.12.006","article-title":"Lessons from the rotenone model of Parkinson\u2019s disease","volume":"31","author":"Greenamyre","year":"2010","journal-title":"Trends Pharmacol. 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