Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi's Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

Abstract

Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson's and Huntington's diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson's and Huntington's disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes.

Figure 1

The PGC-1α cascade. Transcriptional upregulation or posttranslational activation of PGC-1α due to fasting, physical exercise, cold exposure, or pharmacological manipulations leads to the transcriptional activation of several nuclear-encoded proteins involved in mitochondrial functioning at multiple levels, including mitochondrial biogenesis, adaptive metabolism, antioxidant responses, and proper ETC assembly/import.

Figure 2

Schematic representation of the generation and the effects of free radicals within the mitochondria. The leakage of electrons from the mitochondrial ETC at complexes I and III results in the formation of superoxide anion. The high reactivity of this molecule evokes a harmful cascade mechanism including the formation of reactive oxygen and nitrogen species. The cascade mechanism deteriorates the functional groups of major components of all kinds of biomolecules (carbohydrates, lipids, proteins, and nucleic acids). In case of pronounced electron leakage or deficient antioxidant protection, a vicious circle of mitochondrial dysfunction develops.

Figure 3

The detailed depiction of the chemistry of mitochondrial oxidative and nitrative/nitrosative stresses. The contents of the colored bubbles correspond to the processes indicated in the bubbles of the respective color in Figure 2. Figure 3 presents the chemical processes of ETC and the terminal oxidation (white bubble; blue Roman numbers represent the site of the respective respiratory complexes) together with those involved in the generation of ROS (light blue bubble) and RNS (yellow bubble). An overview is given on the most representative molecules involved in oxidative injury to nucleic acids (brown bubble), lipids (pink bubble), and molecules with thiol residues (green bubble), as well as in nitrosylation/nitration of organic macromolecules (yellow bubble). For detailed explanation of oxidative/nitrative/nitrosative (black) and antioxidant (green) processes as well as the function of the ETC (red), we refer to the corresponding sections within the text and the Abbreviations section.

Figure 4

The involvement of mitochondrial dysfunction in Parkinson's disease. Complex I deficiency, the predominant electron transport disorder in sporadic PD has long been linked to the deleterious effects of α-synuclein aggregation, a pathognomonic alteration in PD, and inhibitors of complex I (such as MPTP, rotenone, and paraquat) are used in experimental modeling of the disease. Since then a number of genes have been associated with familial forms of the disease, many of them having direct implications in mitochondrial dysfunction. Disturbed OXPHOS in the affected cells can lead to the development of a vicious circle, eventually leading to cell death. Novel findings link PGC-1α dysfunction to the pathogenesis of sporadic PD, the restoration of which may hold therapeutic value. (↑ = increased presence/expression/activity; ↓ = decreased presence/expression/activity; arrow = promotion; bulb-headed arrow = inhibition/deterioration.)

Figure 5

The involvement of mitochondrial dysfunction in Huntington's disease. Complex II deficiency, the predominant electron transport disorder in HD has long been linked to the deleterious effects of mutant huntingtin aggregation, a pathognomonic alteration in HD, and inhibitors of complex II (such as 3-nitropropionic acid (3-NP) and malonate) are used in experimental modeling of the disease. Disturbed OXPHOS in the affected cells can lead to the development of a vicious circle, eventually leading to cell death. Novel findings link PGC-1α dysfunction to the pathogenesis of HD at multiple levels, the restoration of which may hold therapeutic value. (↑ = increased presence/expression/activity; ↓ = decreased presence/expression/activity; arrow = promotion; bulb-headed arrow = inhibition/deterioration.)