Drug-induced mitochondrial dysfunction and neurotoxicity

Abstract

Mitochondria exerts numerous physiological functions such as energy production and maintainance of calcium homeostasis. The brain is a tissue highly dependent on energy production; 20% of total oxygen consumption is used by the neuron in order to maintain ionic gradients necessary for neurotrasmitters exocytosis, release and uptake. In neurons, mitochondria are distributed to match energetic supply and Ca2+ buffering to the demand imposed by neuronal signaling. Mitochondrial Ca2+ uptake alters the activity of mitochondria, increasing the production of ATP by activating the Ca2+ -sensitive dehydrogenases of the mitochondrial matrix as well as the adenine nucleotide translocator. Mitochondrial calcium overload can activate the production of ROS and can lead ultimately to a cascade of signaling events for initiation of apoptosis or necrosis.Brain mitochondrial function can be assessed either in crude mitochondrial fractions from different brain regions or in isolated synaptosomes and non-synaptic mitochondria from fresh tissues. Mitochondrial dysfunction can be defined as an impairment of the electron transfer activity at the mitochondrial respiratory chain, or inhibition of mitochondrial enzymes necessary for the coupling of electron transfer to ATP synthesis. The uncoupling of the mitochondrial respiratory chain to oxidative phosphorylation can lead to the loss of mitochondrial membrane potential and increased oxygen free radicals generation, resulting in the consequent neuronal damage by induction of apoptotic pathways.Mitochondrial function, calcium homeostasis and oxygen free radicals generation can be affected to different extent and by specific mechanisms by CNS action drugs, such as several antipsychotic and antidepressants. Abuse drugs ethanol and ketamine can act as NMDA antagonists and may exert deleterious effects by targeting mitochondria. Interestingly, several herbicides can be neurotoxic by inducing mitochondrial dysfunction in specific brain areas. The analysis of the effects of CNS action drugs at mitochondrial level can contribute to the understanding of the molecular mechanisms involved in neurodegeneration.Finally, being mitochondria potential drug pharmacological targets, the neuroprotective effect of different compounds targeting mitochondrial integrity and function constitutes a broad subject of research.