Mitochondrial therapy for Parkinson's disease: neuroprotective pharmaconutrition may be disease-modifying

Abstract

Progressive destruction of neurons that produce dopamine in the basal ganglia of the brain, particularly the substantia nigra, is a hallmark of Parkinson's disease. The syndrome of the Parkinsonian phenotype is caused by many etiologies, involving multiple contributing mechanisms. Characteristic findings are pathologic inclusions called Lewy bodies, which are protein aggregates inside nerve cells. Environmental insults are linked with the disease, and a number of associated genes have also been identified. Neuroinflammation, microglia activation, oxidative stress, and mitochondrial dysfunction are central processes producing nerve damage. In addition, protein misfolding, driven by accumulation and condensation of α-synuclein, compounded by inadequate elimination of defective protein through the ubiquitin- proteasome system, promote apoptosis. Current pharmacologic therapy is palliative rather than disease- modifying, and typically becomes unsatisfactory over time. Coenzyme Q10 and creatine, two agents involved in energy production, may be disease-modifying, and able to produce sufficient beneficial pathophysiologic changes in preclinical studies to warrant large studies now in progress. Use of long-chain omega-3 fatty acids and vitamin D in PD are also topics of current interest.

Keywords: Parkinson’s disease; apoptosis; creatine; inflammation; mitochondria; polyunsaturated omega-3 fatty acids; reactive oxygen species; ubiquinone; vitamin D.

Figure 1

Phosphorylation of creatine by creatine kinase to form phosphocreatine in mitochondria.

Figure 2

The structures of ubiquinone (top) and ubiquinol (bottom). Ubiquinone, the oxidized (benzoquinone form of the pair, is 2,3-dimethoxy-5-methyl-6-decaprenyl- 1,4-benzoquinone. Its isoprenoid group (CH₃-CH=C(CH₃)-CH₃) is repeated 10 times in the side chain. Ubiquinol, the reduced (hydroxyl groups at positions 1 and 4 on the benzene ring) form, less two electrons, is 2,3 dimethoxy-5-methyl-6-decaprenyl- 1,4-benzohydroquinol.

Figure 3

Electrons move from food to Krebs cycle intermediates, in a series of oxidation-reduction reactions as they are shuttled through complexes I through IV of the respiratory chain, eventually reaching oxygen. The electron transport chain effecting oxidative phosphorylation is composed of fixed multimeric protein complexes I through V, each with multiple subunits, along the inner mitochondrial membrane, along with two electron carriers, ie, ubiquinone and cytochrome c. As electrons move along the oxidation-reduction complexes I–IV, protons are pumped from the matrix to the intermembrane space by complexes I, II, and IV, creating a proton [H⁺] gradient across the mitochondrial inner membrane. As the protons return to the intermembrane space through complex V (far right, labeled ATP synthase), dissipating the gradient, changes in conformations of enzyme F₁F₀ ATP synthase, which spans the membrane, produce ATP. The inner mitochondrial membrane must remain impermeable to [H⁺] in order to sustain the gradient, which uses about 15% of the total metabolic rate of working tissue. Reproduced with permission of Mariana Ruiz Villarreal, via Wikipedia commons. Abbreviations: CoQ, Coenzyme Q10 (ubiquinone); CoQH, reduced Coenzyme Q10 (ubiquinol); NAD, nicotinamide adenine dinucleotide; AT, adenosine triphosphate; AD, adenosine diphosphate; Cyt c, cytochrome c.