Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells
ABSTRACT Chronic mitochondrial dysfunction, in particular of complex I, has been strongly implicated in the dopaminergic neurodegeneration in Parkinson's disease. To elucidate the mechanisms of chronic complex I disruption-induced neurodegeneration, we induced differentiation of immortalized midbrain dopaminergic (MN9D) and non-dopaminergic (MN9X) neuronal cells, to maintain them in culture without significant cell proliferation and compared their survivals following chronic exposure to nanomolar rotenone, an irreversible complex I inhibitor. Rotenone killed more dopaminergic MN9D cells than non-dopaminergic MN9X cells. Oxidative stress played an important role in rotenone-induced neurodegeneration of MN9X cells, but not MN9D cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and antioxidants decreased rotenone toxicity only in MN9X cells. MN9X cells were also more sensitive to exogenous oxidants than MN9D cells. In contrast, disruption of bioenergetics played a more important role in MN9D cells: rotenone decreased mitochondrial membrane protential and ATP levels in MN9D cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D-beta-hydroxybutyrate, decreased rotenone toxicity in MN9D cells, but not in MN9X cells. MN9D cells were also more susceptible to disruption of oxidative phosphorylation or glycolysis than MN9X cells. These findings indicate that, during chronic rotenone exposure, MN9D cells die primarily through mitochondrial energy disruption, whereas MN9X cells die primarily via oxidative stress. Thus, intrinsic properties of individual cell types play important roles in determining the predominant mechanism of complex I inhibition-induced neurodegeneration.
- SourceAvailable from: Mayumi Prins
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- "Administration of 4 mmol/L β-OHB increased the survival of cultured neurons from 1- methyl-4-phenylpyridinium toxicity (Kashiwaya et al, 2000). Another in vitro model of Parkinson's disease utilizes rotenone, which inhibits mitochondrial complex I. Application of 8 mmol/L β-OHB to this model of Parkinson's increased cell survival, improved mitochondrial membrane potential and reduced cytochrome c release in mouse neuronal cultures (Imamaura et al, 2006), and increased cell survival by 60% in human neuroblastoma cell culture (Kweon et al, 2004). More recently, 24 h infusion of β-OHB in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice showed 45% decrease in motor deficits and a decrease in dopaminergic neurodegeneration (Tieu et al, 2003). "
ABSTRACT: The developing central nervous system has the capacity to metabolize ketone bodies. It was once accepted that on weaning, the 'post-weaned/adult' brain was limited solely to glucose metabolism. However, increasing evidence from conditions of inadequate glucose availability or increased energy demands has shown that the adult brain is not static in its fuel options. The objective of this review is to summarize the body of literature specifically regarding cerebral ketone metabolism at different ages, under conditions of starvation and after various pathologic conditions. The evidence presented supports the following findings: (1) there is an inverse relationship between age and the brain's capacity for ketone metabolism that continues well after weaning; (2) neuroprotective potentials of ketone administration have been shown for neurodegenerative conditions, epilepsy, hypoxia/ischemia, and traumatic brain injury; and (3) there is an age-related therapeutic potential for ketone as an alternative substrate. The concept of cerebral metabolic adaptation under various physiologic and pathologic conditions is not new, but it has taken the contribution of numerous studies over many years to break the previously accepted dogma of cerebral metabolism. Our emerging understanding of cerebral metabolism is far more complex than could have been imagined. It is clear that in addition to glucose, other substrates must be considered along with fuel interactions, metabolic challenges, and cerebral maturation.Journal of Cerebral Blood Flow & Metabolism 02/2008; 28(1):1-16. DOI:10.1038/sj.jcbfm.9600543 · 5.34 Impact Factor
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- "Additionally, the rotenone induced-degeneration of dopaminergic neurons in the nigrostriatal region may also be attributed to the activation of microglia, the resident macrophages in the brain, in response to the widespread oxidative damage provoked by rotenone [Gao et al., 2002; 2003; Sherer et al., 2003a]. In cell culture models, inhibition of complex I with rotenone causes cell death in a variety of cell types, including dopaminergic and non-dopaminergic neurons, via distinct mechanisms [Kweon et al., 2004]. The multiple effects caused by rotenone on cell survival and integrity triggers the assumption that the common use/exposure to rotenone may be a risk factor contributing to the development of neurodegenerative diseases. "
ABSTRACT: Animal models treated with agricultural chemicals, such as rotenone, reproduce several degenerative features of human central nervous system (CNS) diseases. Glutamate is the most abundant excitatory amino acid transmitter in the mammalian central nervous system and its transmission is implicated in a variety of brain functions including mental behavior and memory. Dysfunction of glutamate neurotransmission in the CNS has been associated with a number of human neurodegenerative diseases, either as a primary or as a secondary factor in the excitotoxic events leading to neuronal death. Since many human CNS disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by toxic agents. Candidate environmental toxins bearing any direct or indirect effects on the pathogenesis of human disease are particularly useful. The present longitudinal Magnetic Resonance Imaging (MRI) studies show, for the first time, significant variations in the properties of brain ventricles in a rotenone-treated (2 mg/kg) mouse model over a period of 4 weeks following 3 days of rotenone treatment. Histopathological analysis reveals death of stria terminalis neurons following this short period of rotenone treatment. Furthermore, in vivo voxel localized (1)H MR spectroscopy also shows for the first time significant bio-energetic and metabolic changes as well as temporal alterations in the levels of glutamate in the degenerating striatal region. These studies provide novel insights on the effects of environmental toxins on glutamate and other amino acid neurotransmitters in human neurodegenerative diseases.Experimental Neurology 02/2008; 209(1):224-33. DOI:10.1016/j.expneurol.2007.09.023 · 4.62 Impact Factor
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- "The expressions of genes involved in protein catabolism, apoptosis, and oxidative stress are not significantly different between SN and VTA. Another study found that mitochondrial complex I inhibition may lead to energy stress in dopaminergic neurons whereas the same insult results in oxidative stress in nondopaminergic neurons (Kweon et al., 2004). "
ABSTRACT: Cell biology of PINK1, a protein mutated in a recessive form of Parkinson's disease