Role of mitochondria in the etiology and pathogenesis of Parkinson's disease

Abstract

We discuss the etiology and pathogenesis of Parkinson's disease (PD). Our group and others have found a decrease in complex I of the mitochondrial electron transfer complex in the substantia nigra of patients with PD; in addition, we reported loss of the alpha-ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra. Dual loss of complex I and the KGDHC will deleteriously affect the electron transport and ATP synthesis; we believe that energy crisis is the most important mechanism of nigral cell death in PD. Oxidative stress has also been implicated as an important contributor to nigral cell death in PD, but we believe that oxidative stress is a secondary phenomenon to respiratory failure, because respiratory failure will increase oxygen free-radical formation and consume glutathione. The primary cause of mitochondrial respiratory failure has not been elucidated yet, but additive effect of environmental neurotoxins in genetically predisposed persons appears to be the most likely possibility.

Immunochemical Characterization of the Deficiency of the α‐Ketoglutarate Dehydrogenase Complex in Thiamine‐Deficient Rat Brain

“…KGDHC is deficient in brains from individuals with Wernicke-Korsakoff '5 syndrome (Butterworth eta!., 1993), A!zheimer's disease (Gibson et a!., 1988;Mastrogiacomo et a!., 1996b), Parkinson's disease (Mizuno et a!., 1994(Mizuno et a!., , 1995, and hereditary ataxias (Mastrogiacomo and Kish, 1994;Mastrogiacomo eta!., 1996a). WernickeKorsakoff 's syndrome is caused by TD (McCandless, 1985;Victor eta!., 1989).…”

“…Reduction of the mitochondrial ThDP-dependent a-ketoglutarate dehydrogenase complex (KGDHC) is associated with many age-dependent neurodegenerative diseases in which a deficit of cerebral metabolic rates is a prominent feature (Blass, 1993;Beal, 1995). These diseases include Alzheimer's disease (Gibson et a!., 1988;Mastrogiacomo et a!., 1996b), Parkinson's disease (Mizuno et al, 1994(Mizuno et al, , 1995, Friedreich's and type-i hereditary spinocerebellar ataxias (Mastrogiacomo and Kish, 1994;Mastrogiacomo et a!., 1996a), and Wemicke-Korsakoff 's syndrome . These findings have led to the proposal that KGDHC may play a common ro!e in these neurodegenerative conditions and that e!ucidating the mo!ecular events underlying the abnorma!ity of KGDHC may help to understand the ro!e of mitochondria!…”

Reduction in the E2k Subunit of the α-Ketoglutarate Dehydrogenase Complex Has Effects Independent of Complex Activity

“…Alzheimer's disease (AD) (1-4), Parkinson's disease (5)(6)(7)(8), progressive supranuclear palsy (9 -10), and Wernicke-Korsakoff syndrome (11). The reduction in KGDHC activities in brains from AD patients bearing one apolipoprotein E4 allele is highly correlated to a clinical dementia rating (12).…”

Inhibition of α-ketoglutarate-and pyruvate dehydrogenase complexes in E. coli by a glutathione S-transferase containing a pathological length poly-Q domain: A possible role of energy deficit in neurological diseases associated with poly-Q expansions?

“…Defects of energy metabolism are well documented to occur in the brains of patients with Alzheimer disease (AD) (reviewed in 18-21), Huntington's disease (HD) (21 and references therein) and Parkinson' disease (22). KGDHC and PDHC activities are reduced in AD brain (23)(24)(25).…”

“…PDHC activity is reduced in HD brain (21), and KGDHC activity is reduced in cerebella of patients with spinocerebellar ataxia type I (28). KGDHC activity is decreased in affected regions of Parkinson's disease brain, possibly due to loss of neurons (22,29). Finally, the activities of KGDHC, PDHC and several other mitochondrial enzymes involved in energy metabolism are reduced in the brains of patients with several hereditary ataxias (30).…”