Mitochondria in Huntington's disease: implications in pathogenesis and mitochondrial-targeted therapeutic strategies

Abstract

Huntington's disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4. Compelling evidence implicates impaired mitochondrial energetics, altered mitochondrial biogenesis and quality control, disturbed mitochondrial trafficking, oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder. Unfortunately, conventional mitochondrial-targeted molecules, such as cysteamine, creatine, coenzyme Q10, or triheptanoin, yielded negative or inconclusive results. However, future therapeutic strategies, aiming to restore mitochondrial biogenesis, improving the fission/fusion balance, and improving mitochondrial trafficking, could prove useful tools in improving the phenotype of Huntington's disease and, used in combination with genome-editing methods, could lead to a cure for the disease.

Keywords: Huntington’s disease; SS peptides; antioxidants; calcium homeostasis; mitochondrial biogenesis; mitochondrial fission/fusion; mitochondrial trafficking; oxidative phosphorylation; oxidative stress; therapeutic intervention.

Figure 1

Impaired calcium homeostasis in Huntington’s disease leads to apoptosis. Mutant Htt enhances the function of NMDA receptors (NMDAR) most likely through decreased interaction with postsynaptic density 95 (PDS95). The result is increased calcium influx. Dopamine released by nigral neurons acts on D1 and D2 receptors (D1R and D2R) and directly (for D2Rs) or indirectly (via activation of adenyl cyclase and phosphokinase A - for D1Rs) stimulate inositol 1,4,5-phosphate receptors (IP3R), leading to further increases of cytosolic Ca²⁺ concentrations by stimulating Ca²⁺ release from the endoplasmic reticulum (ER). The excess cytosolic calcium is buffered by mitochondria via the mitochondrial voltage-gated anion channel (VDAC) and mitochondrial calcium uniporter. However, mitochondrial Ca²⁺ overload will cause opening of the mitochondrial permeability transition pore (MPTP). This outcome is enhanced by the direct association of mHtt with mitochondrial membrane proteins. VGCC: L-type voltage-gated calcium channel.