Involvement of Akt/mTOR in the Neurotoxicity of Rotenone-Induced Parkinson’s Disease Models

Abstract

Rotenone has recently been widely used to establish Parkinson’s disease (PD) models to replicate the features of PD. However, the mechanisms involved in rotenone neurotoxicity have not been elucidated. The aim of the present study was to identify the neurotoxicity of rotenone through intraperitoneal injection in mice and to investigate the global changes of phosphorylation proteomic profiles in rotenone-injured SH-SY5Y cells through a label-free proteomic analysis using a PTMScan with LC–MS/MS. ICR (Institute of Cancer Research) mice were intraperitoneally injected with different dosages of rotenone (1 mg/kg/d or 3 mg/kg/d) daily for 21 consecutive days. Rotenone caused a dose-dependent decrease in locomotor activities and a decrease in the number of Nissl-positive and tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra pars compacta (SNpc). Here, 194 phosphopeptides on 174 proteins were detected in SH-SY5Y cells, and 37 phosphosites on 33 proteins displayed statistically significant changes in expression after rotenone injury. The downregulation of phosphorylated Akt and mTOR was further confirmed by western blot analysis. A specific Akt activator, SC79, could protect cell viability and induce autophagy in rotenone-injured SH-SY5Y cells. This study indicates the involvement of the Akt/mTOR (mammalian target of rapamycin) signaling pathway in rotenone-injured SH-SY5Y cells and provides molecular information for the neurotoxicity of rotenone.

β-Cells Different Vulnerability to the Parkinsonian Neurotoxins Rotenone, 1-Methyl-4-phenylpyridinium (MPP+) and 6-Hydroxydopamine (6-OHDA)

“…We found comparable evidence for MPP + at high concentration, while 6-OHDA produced alterations mostly to the ER and the nucleus. Similar changes have been previously reported in neuronal cell lines in the presence of these neurotoxins [ 27 , 47 , 48 ].…”

“…It determines the block of oxidative phosphorylation [ 25 ] and the flow of electrons to oxygen thereby increasing the production of reactive oxygen species (ROS) [ 26 ]. Other possible mechanisms of toxicity are associated to interference with PI3K/Akt/mTOR-related signaling [ 27 ] and microtubules dynamics [ 28 ].…”

Pyrroloquinoline Quinone Inhibits Rotenone-Induced Microglia Inflammation by Enhancing Autophagy

“…Moreover, PQQ was reported to stimulate mitochondrial biogenesis and might be beneficial in diseases associated with mitochondrial dysfunction [ 42 ]. We also demonstrated that activation of Akt/mTOR signaling pathway in rotenone-injured SH-SY5Y cells could induce autophagy and protect the cells [ 22 ]. Together, this evidence suggested that rotenone might disrupt mitochondrial functions, thus, leading to autophagy defects and inflammation activation, while PQQ pretreatment could rescue the injury by regulating mitochondrial functions and oxidative stress.…”

“…The modulation of autophagy is responsible for inflammatory processes in many diseases through regulating pro-inflammatory factors production [ 21 ]. Our previous study indicated that Akt/mTOR pathway activation might induce autophagy and protect against rotenone-induced SH-SY5Y cells injury [ 22 ]. Additionally, PI3K/Akt pathway can be activated by PQQ pretreatment in cultured midbrain neurons [ 6 ].…”

Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment

“…In our in vitro experiments, rotenone, a well-known complex I inhibitor, strongly exhibited adverse toxicity, whereas metformin had a weak effect on tumor growth. Rotenone also inhibits myotube formation, which can have neurotoxic effects (Liu et al, 2005;Zhang et al, 2019). The limitations of metformin for cancer treatment, including inadequate potency and transport-mediated accumulation, have been previously reported (Wang et al, 2002).…”