Neuroprotective Effects of the Neural-Induced Adipose-Derived Stem Cell Secretome against Rotenone-Induced Mitochondrial and Endoplasmic Reticulum Dysfunction.

ABSTRACT

Mesenchymal stem cells (MSCs) have therapeutic effects on neurodegenerative diseases (NDDs) known by their secreted molecules, referred to as the "secretome". The mitochondrial complex I inhibitor, rotenone (ROT), reproduces α-synuclein (α-syn) aggregation seen in Parkinson's 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-IRE1α, 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.