Abstract
Parkinson’s disease is characterized by dopaminergic neurodegeneration and is associated with mitochondrial dysfunction. The bioenergetic susceptibility of dopaminergic neurons to toxins which induce Parkinson’s like syndromes in animal models is then of particular interest. For example, rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+), and 6-hydroxydopamine (6-OHDA), have been shown to induce dopaminergic cell death in vivo and in vitro. Exposure of animals to these compounds induce a range of responses characteristics of Parkinson’s disease, including dopaminergic cell death, and Reactive Oxygen Species (ROS) production. Here we test the hypothesis that cellular bioenergetic dysfunction caused by these compounds correlates with induction of cell death in differentiated dopaminergic neuroblastoma SH-SY5Y cells. At increasing doses, rotenone induced significant cell death accompanied with caspase 3 activation. At these concentrations, rotenone had an immediate inhibition of mitochondrial basal oxygen consumption rate (OCR) concomitant with a decrease of ATP-linked OCR and reserve capacity, as well as a stimulation of glycolysis. MPP+ exhibited a different behavior with less pronounced cell death at doses that nearly eliminated basal and ATP-linked OCR. Interestingly, MPP+, unlike rotenone, stimulated bioenergetic reserve capacity. The effects of 6-OHDA on bioenergetic function was markedly less than the effects of rotenone or MPP+ at cytotoxic doses, suggesting a mechanism largely independent of bioenergetic dysfunction. These studies suggest that these dopaminergic neurotoxins induce cell death through distinct mechanisms and differential effects on cellular bioenergetics.
Highlights
Parkinson’s disease is the second most common neurodegenerative disease, affecting over 4 million people with pronounced degeneration of the dopaminergic neurons of the substantia nigra [1]
Neurotoxin models play an important role in Parkinson’s research and the compounds described here have been used by many researchers with isolated mitochondria, cultured cells and animal models of the disease [15,16,45,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85]
In this study we provide data which bridges the gap between experiments with rotenone, MPP+ and 6-OHDA in isolated mitochondria, with cell and animal models by assessment of cellular bioenergetics
Summary
Parkinson’s disease is the second most common neurodegenerative disease, affecting over 4 million people with pronounced degeneration of the dopaminergic neurons of the substantia nigra [1]. Mitochondrial dysfunction has been proposed to play a major role in Parkinson’s disease pathogenesis and can be induced by both exogenous and endogenous neurotoxins [2]. The mitochondrial enzyme which has been most frequently implicated in Parkinson’s disease is complex I [2]. Dysfunction of this complex has been shown in mitochondria isolated from postmortem brains, skeletal muscle and platelets of Parkinson’s disease patients [3,4,5,6,7,8,9,10]. Cybrid cell lines with mitochondria from Parkinson’s disease patients exhibit decreased complex I activity [9,11,12,13,14]
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