In vivo vulnerability of dopamine neurons to inhibition of energy metabolism
Introduction
Dopamine neurons in the substantia nigra pars compacta and their axonal projections in the striatum are the primary neurotransmitter population lost in Parkinson's disease. Recent studies from several laboratories have demonstrated mitochondrial defects in Parkinson's disease. In some studies, the defects were specific to the substantia nigra (Mizuno et al., 1989; Schapira et al., 1989, Schapira et al., 1990; Mann et al., 1992), while in others, a more generalized impairment involving muscle and platelet mitochondria was observed (Parker et al., 1989; Shoffner et al., 1991; Bindoff et al., 1991; Benecke et al., 1993). At present, it is not known whether mitochondrial defects are a cause or an effect of Parkinson's disease. Also not known is the reason for the specific targeting of dopamine neurons should a generalized mitochondrial defect be found to be an underlying cause of the disease. Understanding how mild to moderate metabolic stress affects dopamine neurons, however, may provide insight into the loss of these neurons in Parkinson's disease.
The greater vulnerability of mesencephalic dopamine neurons to impairment of energy metabolism has been suggested by several findings. The loss of high affinity uptake of dopamine in synaptosomal preparations was demonstrated to be more sensitive to acute rotenone (mitochondrial complex I inhibitor), antimycin A (complex III inhibitor) and cyanide (complex IV inhibitor) treatment as compared with norepinephrine, γ-aminobutyric acid (GABA) and serotonin uptake suggesting that a constitutive metabolic deficiency existed in dopamine versus other neurotransmitter populations (Marey-Semper et al., 1993). Dopamine neurons in mouse mesencephalic cultures were three times more sensitive than mesencephalic GABA neurons or striatal GABA or cholinergic neurons to a sequential exposure to rotenone and glutamate (Marey-Semper et al., 1995, Marey-Semper et al., 1995), also suggesting an inherent vulnerability of dopamine neurons to energy impairment. Consistent with the findings of Marey-Semper et al. (1993), Marey-Semper et al. (1995), our laboratory recently reported that dopamine neurons in rat mesencephalic culture were more sensitive to a mild metabolic stress produced by inhibiting the Krebs cycle enzyme succinate dehydrogenase with the reversible, competitive inhibitor, malonate (Zeevalk et al., 1995). The purpose of the present work was to examine the relative vulnerability of dopamine neurons in vivo to energy impairment. Sensitivity to malonate was examined at the level of the cell body in the nigra and at its axonal projection sites in the striatum. In each case, the vulnerability of the dopamine population to malonate was compared with the GABA population.
Section snippets
Animal handling and treatment
Male Sprague-Dawley rats (350–400 g; approximately 3–4 months; Harlan Farms, Indianapolis, IN, USA) were used in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All procedures were approved by the local Animal Care Committee. Rats were grouped 2 per cage in a room maintained at 20–22°C on a 12-h light-dark cycle with food and water available ad libitum. Animals were anesthetized with Brevital (16.7 mg/kg). Vehicle (saline, pH 7.6) or malonate
Results
Injection of 4-month-old rats with various amounts of malonate into the left substantia nigra produced a similar loss of nigral dopamine and GABA when assayed 1 week after the injection (Fig. 1A). The 50% dose level for malonate-induced loss of dopamine and GABA was 0.39 or 0.42 μmol, respectively. Animals that received greater than 1 μmol malonate had excessive tissue destruction and cavitation in the mesencephalon and were eliminated from the study. Injection of vehicle (saline, pH 7.4) did
Discussion
In the last few years, many laboratories have reported deficiencies in energy metabolism in patients with Parkinson's disease, thus positing inefficient energy metabolism as a possible cause of the loss of nigral dopamine neurons in this disease (Beal, 1992; DiMauro, 1993). In several of these studies (Parker et al., 1989; Shoffner et al., 1991; Bindoff et al., 1991; Benecke et al., 1993), deficits have been reported in the mitochondria isolated from blood platelets and muscle from Parkinson
Acknowledgements
The authors would like to thank Nina Jocnowitz for her technical assistance. This work was supported by a National Parkinson Foundation Grant.
References (32)
- Albers, D.S., G.D. Zeevalk and P.K. Sonsalla, 1996, Damage to dopaminergic nerve terminals in mice by combined...
- Beal, M.F., 1992, Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative...
- Beal, M.F., E. Brouillet, B. Jenkins, R. Henshaw, B. Rosen and T. Hyman, 1993a, Age dependent striatal excitotoxic...
- Beal, M.F., E. Brouillet, B.G. Jenkins, R.J. Ferrante, N.W. Kowall, J.M. Miller, E. Storey, R. Srivastava, B.R. Rosen...
- Benecke, R., P. Strumper and H. Weiss, 1993, Electron transfer complexes I and IV of platelets are abnormal in...
- Bindoff, L.A., M.A. Birch-Machin, N.E.F. Cartidge, W.D. Parker and D.M. Turnbull, 1991, Respiratory chain abnormalities...
- Brouillet, E., B.G. Jenkins, B.T. Hyman, R.J. Ferrante, N.W. Kowall, R. Srivastava, D.S. Roy, B.R. Rosen and M.F. Beal,...
- DiMauro, S., 1993, Mitochondrial involvement in Parkinson's disease: the controversy continues, Neurology 43,...
- Graham, D.G., S.M. Tiffany, W.R. Bell Jr. and W.F. Gutknecht, 1978, Autoxidation versus covalent binding of quinones as...
- Greene, J.G., R.H.P Porter, R.V. Eller and J.T. Greenamyre, 1993, Inhibition of succinate dehydrogenase by malonic acid...
Cited by (44)
Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism
2019, Advances in Biological RegulationThe Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency
2017, Cell Chemical BiologyCitation Excerpt :Malonate is an endogenous metabolite that acts as a classic competitive inhibitor of SDH (Quastel and Wooldridge, 1928). As such, malonate is cytotoxic by blocking cellular respiration, and the effects of malonate are especially detrimental in cells that rely heavily on oxidative metabolism (Beal et al., 1993; Moy et al., 2000; Zeevalk et al., 1997). To determine if loss of ACSF3 would exacerbate malonate-induced toxicity, ACSF3 KO and control cells were treated with increasing concentrations of malonate and cell survival was assayed after 72 hr of exposure (Figure S1C).
Analysis of regional brain mitochondrial bioenergetics and susceptibility to mitochondrial inhibition utilizing a microplate based system
2011, Journal of Neuroscience MethodsCitation Excerpt :Multiple groups have further established that in addition to brain region differences in mitochondrial function there is a significant difference between synaptic and non-synaptic mitochondria (Davey et al., 1997; Brown et al., 2006; Naga et al., 2007; Pathak and Davey, 2008). Numerous factors are likely to play role in the differential susceptibility of mitochondria such as which region of the brain the mitochondria are from (Singh et al., 2010), which portion of the CNS the mitochondria are from (Sullivan et al., 2004), or the energy demands of the cell containing the mitochondria (Zeevalk et al., 1997). In order to further elucidate the role of the mitochondria in regionally specific toxin susceptibility, analysis of basal mitochondrial function was performed across various regions of the brain.
Acute and Chronic Administration of 1-Methyl-4-Phenylpyridinium
2008, Parkinson's Disease