Mitochondrial diseases of the brain

Abstract

Neurodegenerative disorders are debilitating diseases of the brain, characterized by behavioral, motor and cognitive impairments. Ample evidence underpins mitochondrial dysfunction as a central causal factor in the pathogenesis of neurodegenerative disorders including Parkinson's disease, Huntington's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Friedreich's ataxia and Charcot-Marie-Tooth disease. In this review, we discuss the role of mitochondrial dysfunction such as bioenergetics defects, mitochondrial DNA mutations, gene mutations, altered mitochondrial dynamics (mitochondrial fusion/fission, morphology, size, transport/trafficking, and movement), impaired transcription and the association of mutated proteins with mitochondria in these diseases. We highlight the therapeutic role of mitochondrial bioenergetic agents in toxin and in cellular and genetic animal models of neurodegenerative disorders. We also discuss clinical trials of bioenergetics agents in neurodegenerative disorders. Lastly, we shed light on PGC-1α, TORC-1, AMP kinase, Nrf2-ARE, and Sirtuins as novel therapeutic targets for neurodegenerative disorders.

Keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydrodropyridine; 1-methyl-4-phenylpyridinium; 6-OHDA; 6-hydroxydopamine; AD; ALS; AMP-activated protein kinase; AMPK; Alzheimer’s disease; Amyotrophic Lateral Sclerosis; Amyotrophic lateral sclerosis; BAT; CK; Charcot-Marie-Tooth disease and Friedreich’s ataxia; Co-Q10; CoQ10; Creatine; Drp1; Free radicals; HD; Huntington’s Disease; Huntington’s disease; KGDH; MFN; MMP; MPP+; MPTP; Mitochondrial dysfunction; Neurodegenerative diseases; PCr; PD; PGC-1α; PPARs; Parkinson’s disease; ROS; Sirtuins; TAR DNA; TCA; TORC; Tfam; Transduceres of Creb-related binding protein; UCP-1; alpha-ketoglutarate dehydrogenase; binding protein TDP-43; brown adipose tissue; coenzymeQ10; creatine kinase; dynamin-related protein 1; mitochondrial DNA; mitochondrial membrane potential; mitochondrial transcription factor A; mitofusin; mtDNA; peroxisome proliferator-activated receptors; phosphocreatine; proliferator-activated receptor-gamma coactivator-1alpha; reactive oxygen species; tricarboxylic acid cycle; uncoupling proteins.