Mitochondria: a therapeutic target in neurodegeneration

Abstract

Mitochondrial dysfunction has long been associated with neurodegenerative disease. Therefore, mitochondrial protective agents represent a unique direction for the development of drug candidates that can modify the pathogenesis of neurodegeneration. This review discusses evidence showing that mitochondrial dysfunction has a central role in the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. We also debate the potential therapeutic efficacy of metabolic antioxidants, mitochondria-directed antioxidants and Szeto-Schiller (SS) peptides. Since these compounds preferentially target mitochondria, a major source of oxidative damage, they are promising therapeutic candidates for neurodegenerative diseases. Furthermore, we will briefly discuss the novel action of the antihistamine drug Dimebon on mitochondria.

Figure 1. The two faces of mitochondria

Besides the fundamental role of mitochondria in the generation of energy (ATP), these organelles are also the main producers of reactive oxygen species (ROS). If ROS levels overwhelm the defense mechanisms of the cells, oxidative damage of proteins, lipids and DNA occurs. Besides other constituents of the cells, mitochondria are highly affected by oxidative damage leading to the impairment of ATP production. Other consequences of mitochondria impairment is the opening of the permeability transition pore and release of pro-apoptotic factors that ultimately contributes to cell degeneration and death. Consequently, it is unsurprising that mitochondrial oxidative damage is intimately involved in neurodegenerative diseases. Although ROS are traditionally viewed as toxic agents contributing to cellular pathology, emerging evidence suggests that low/moderate levels of ROS are involved in survival and regulation pathways being critical in cellular homeostasis. H₂O₂, hydrogen peroxide; hydroxyl radical, HO•, GPx, glutathione peroxidase; GRed, glutathione reductase; GSH, reduced glutathione; O₂•⁻, superoxide anion radical; SOD, superoxide dismutase

Figure 2. Mitochondrial-directed therapies

Metabolic antioxidants (creatine, α-lipoic acid, N-acetyl-carnitine and coenzyme Q10) are involved in cellular energy production and act as cofactors of several metabolic enzymes. Additionally, they have also potent antioxidant actions avoiding damage of lipids, proteins and DNA. Mitochondria-targeted antioxidants and SS peptides selectively accumulated into mitochondria, a major source of reactive oxygen species (ROS) protecting against oxidative damage of mitochondrial and cellular components. Dimebon binds to NMDA receptors on the outside of the cell and decreases glutamate influx. It also binds Ca²⁺ channels and prevents an influx of Ca²⁺ from entering the cell. Recent evidence shows that Dimenbon stabilizes mitochondria by preventing the opening of the permeability transition pore.