Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases

Abstract

The pesticide rotenone, a neurotoxin that inhibits the mitochondrial complex I, and destabilizes microtubules (MT) has been linked to Parkinson disease (PD) etiology and is often used to model this neurodegenerative disease (ND). Many of the mechanisms of action of rotenone are posited mechanisms of neurodegeneration; however, they are not fully understood. Therefore, the study of rotenone-affected functional pathways is pertinent to the understanding of NDs pathogenesis. This report describes the transcriptome analysis of a neuroblastoma (NB) cell line chronically exposed to marginally toxic and moderately toxic doses of rotenone. The results revealed a complex pleiotropic response to rotenone that impacts a variety of cellular events, including cell cycle, DNA damage response, proliferation, differentiation, senescence and cell death, which could lead to survival or neurodegeneration depending on the dose and time of exposure and cell phenotype. The response encompasses an array of physiological pathways, modulated by transcriptional and epigenetic regulatory networks, likely activated by homeostatic alterations. Pathways that incorporate the contribution of MT destabilization to rotenone toxicity are suggested to explain complex I-independent rotenone-induced alterations of metabolism and redox homeostasis. The postulated mechanisms involve the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin, which coupled with other rotenone-induced organelle dysfunctions may underlie many presumed neurodegeneration mechanisms associated with pathophysiological aspects of various NDs including PD, AD and their variant forms. Thus, further investigation of such pathways may help identify novel therapeutic paths for these NDs.

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

“…Although the present results implicate the respiratory chain in signal transduction, identification of a subunit with a functional ITAM would establish the respiratory chain as a bona fide signal transducer. Such a subunit might also mediate some of the many functions of the respiratory chain described that are independent of its ability to produce ATP (59,(76)(77)(78). The present data suggesting mitochondrial intermembrane space localization of the Syk pathway also raise the question of whether Syk and Lyn might directly tyrosine-phosphorylate and modulate respiratory chain function.…”

Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis

“…2A. In the first study21 (GSE35642), after one week of treatment with two different concentrations of rotenone (5 nM and 50 nM), there was a higher number of up-regulated lysosomal genes, suggesting an overall increase in lysosomal biogenesis (Supplementary Figure 2A). However, after four weeks of treatment the effect was completely reversed, with a much higher number of lysosomal genes being down-regulated (Supplementary Figure 2A).…”

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

“…These abnormalities can trigger apoptotic cell death as well [42]. Further, the pesticide rotenone which is known to inhibit mitochondrial complex I in PD is also responsible for microtubule (MT) destabilization that contributes to the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin and thus leads to PD [43]. Upcoming research identified hepatic mitochondrial dysfunctions in a rodent model of PD that arise as a result of nigrostriatal degeneration and interference in CNS-liver interaction due to thyroid hormone [44].…”