Perspectives of drug-based neuroprotection targeting mitochondria

Abstract

Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet.

Keywords: 5-aminoimidazole-4-carboxamide ribonucleoside; AD; AICAR; ALS; AMP; ATP; Acide N-methyl-D-aspartic; Adenosine monophosphate; Adenosine triphosphate; Alzheimer's disease; Amyotrophic lateral sclerosis; CCCP; CNS; Carbonylcyanide m-chlorophenylhydrazone; Central nervous system; CoQ; Coenzyme Q; Cyclic AMP; ERR; ETC; Electron transport chain; Estrogen-related receptors; FAD/FADH; Flavin adenine nucleotide; GDAP1; Ganglioside-induced differentiation-associated protein 1; HD; Huntington disease; KTP; Kinetin triphosphate; LHON; Leber hereditary optic neuropathy; MAPK; MELAS; MERRF; MFN1/MFN2; Maladies mitochondriales; Maladies neurodégénératives; Mammalian target of rapamycin; Manganese superoxide dismutase; Mitochondria; Mitochondrial diseases; Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; Mitochondrial genome or DNA; Mitochondrial permeability transition pore; Mitochondrial transcription factor A; Mitochondrie; Mitofusin; Mitogen-activated protein kinases; MnSOD; Myoclonic epilepsy and ragged red fibers; NAD/NADH; NARP; NMDA; NOS; NRF1/NRF2; Neurodegenerative disorders; Neurogenic muscle weakness, ataxia, and retinitis pigmentosa; Neuroprotection pharmacologique; Nicotinamide adenine dinucleotide; Nitric oxide synthase; Nuclear genome or DNA; Nuclear respiratory factors; OPA1; OXPHOS; Optic atrophy 1; Oxidative phosphorylation; PARL; PD; PGC-1-α; PGC1-related coactivator; PINK1; PKA; PPAR; PPAR gamma coactivator 1-alpha; PRC; PTEN-induced putative kinase1; Parkinson's disease; Peroxisome proliferators-activated receptors; Pharmacological neuroprotection; Presenilins-associated rhomboid-like protein; Protein kinase A; RC; ROS; RXR; Reactive oxygen species; Respiratory chain; Retinoid X receptors; SIRT; Sirtuins; TFAM; TFB2/TFB2; Transcription factors B1 and B2; cAMP; mTOR; mtDNA; mtPTP; nDNA.