Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism.
The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism.
School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68516, United States; Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68503, United States.
Annadurai
A
Anandhan
School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68516, United States.
Maria S
MS
Jacome
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68503, United States.
Shulei
S
Lei
School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68516, United States; Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68503, United States.
Pablo
P
Hernandez-Franco
Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus, Dragana, 68100 Alexandroupolis, Greece.
Aglaia
A
Pappa
School of Life Sciences, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, UK.
Mihalis I
MI
Panayiotidis
Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68503, United States; Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68503, United States.
Robert
R
Powers
School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68516, United States; Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68503, United States. Electronic address: rfrancocruz2@unl.edu.
Rodrigo
R
Franco
D001921:Brain / Q000378:metabolism; D001928:Brain Diseases, Metabolic; D002244:Carbon / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D004734:Energy Metabolism; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism
D002244:Carbon
Bioenergetics; Glucose; Glycolysis; Mitochondria; Neurodegeneration; Oxidative stress; TCA cycle