Matrix

All About Parkinson's Disease

All About Parkinson's Disease

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FIGURE 1 Schematic diagram of the mitochondrial ETC. Note the site of complex I inhibition by rotenone and MPP+, electron leakage and ROS production. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; ETC, electron transport chain; FAD, flavin adenine dinucleotide; FADH2, flavin adenine dinucleotide; MPP, 1-methyl-4-phenyl-2,3-dihydropyridinium ion; NADH, nico-tinamide dinucleotide; ROS, reactive oxygen species; TCA, trycarboxylic acid.

FIGURE 1 Schematic diagram of the mitochondrial ETC. Note the site of complex I inhibition by rotenone and MPP+, electron leakage and ROS production. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; ETC, electron transport chain; FAD, flavin adenine dinucleotide; FADH2, flavin adenine dinucleotide; MPP, 1-methyl-4-phenyl-2,3-dihydropyridinium ion; NADH, nico-tinamide dinucleotide; ROS, reactive oxygen species; TCA, trycarboxylic acid.

selectively permeable to ions and the control of its permeability is the key to most mitochondrial functions, including oxphos, intracellular calcium regulation, apop-tosis, and cell death. Oxphos consists of two closely coupled processes: electron transport to oxygen and phosphorylation of adenosine diphosphate (ADP). Electrons from NADH enter the ETC via complex I (NADH dehydrogenase or NADH-ubiquinone oxidoreductase). Complex I is composed of 46 subunits, seven of which are mitochondrially encoded. Rotenone and 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPP+) are known inhibitors (Fig. 1) of this enzyme (32,33). Electrons from complex I are transferred to complex III (ubiquinol-cytochrome c oxidoreductase) via ubiquinone. Ubiquinone also receives electrons from FADH2 most of which is generated by the TCA cycle. From complex III, the electrons are donated to cytochrome c that transfer them to complex IV. Complex IV transfers electrons to molecular oxygen, the final electron acceptor. Complexes I, III, and IV pump protons from the inner mitochondrial matrix to the outer mitochondrial matrix, creating potential energy, stored in the form of an electrochemical gradient. These protons flow back into the matrix through complex V or ATP synthase and provide the energy needed for ATP production (34). Knowledge that human brain contributes 2% of the body weight but produces 20% of ATP confirms the importance of oxphos (35).

As mentioned previously PD has been associated with a systemic but modest complex I inhibition. Schapira and his colleagues first reported selective complex I defects (other complexes were not affected) in substantia nigra of PD patients (20). Later on, reports indicated that the complex I defect is systemic in PD, affecting tissues outside the brain such as platelets, lymphocytes, and muscle (19,21,36-40). The nature of this complex I defect—whether genetic or acquired—remains uncertain. The role of mitochondria in PD has been further accentuated by the observation that MPP+, the active metabolite of l-methyl-4-phenyl-l,2,3,6-tetrahydro-pyridine (MPTP) and an inhibitor of complex I of the mitochondrial electron transport chain, causes an acute parkinsonian syndrome (32,41,42).

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