Brain mitochondria bioenergetics, nitrergic and neurotensinergic systems

Abstract

Mitochondria display a central role in cellular activity, being essential for energetic metabolism, Ca2+ homeostasis and cell signalling. The brain is one of the organs with the highest oxygen consumption of the human body, which is employed, in great proportion, to maintain and restore ionic equilibria through neuronal membranes in resting conditions and after the passage of the nervous impulse. Furthermore, neurons rely almost exclusively on ATP synthesis from the mitochondrial respiratory chain and oxidative phosphorylation to fulfill their energy requirements for neurotransmitter synthesis, release and reuptake. Differences between the characteristics of astrocyte and neuron mitochondria are evident such as for instance the distribution and organization of supercomplex respiratory chain components. In addition, some differences between oligodendrocytes and astrocytes bioenergetics have been reported.According to their distribution within the neurons, mitochondria are termed synaptic, when located within the nerve endings and non-synaptic ones, when present in neuronal soma. Environmental and energy demand differences for synaptic mitochondria versus non-synaptic mitochondria are apparent. Nitric oxide (NO) is a free radical that acts as an intercellular messenger in physiological processes such as neurotransmission, among other functions. Nitric oxide is generated by the activity of three NO synthase (NOS) enzyme isoforms. One of them, the neuronal NOS (nNOS) predominates in neuronal tissue. At central nervous system, besides the so-called classic neurotransmitters, a constellation of peptides have been identified. They present pharmacological characteristics and are colocalized and coreleased together with the classic neurotransmitters.Neurotensin is a tridecapeptide which at both central and peripheral nervous systems exerts a wide spectrum of effects. Neurotensin acts as a neuromodulator or as a neurotransmitter through its binding to specific receptors. The most important receptors are coupled to G protein, and are termed NTS1 and NTS2, which bind respectively the peptide with high and low affinity.When neurotensin binds to NTS2 receptor, it exerts either agonist or antagonist activity, according to this receptor-mediated pathway. The blockade of NTS2 receptor by levocabastine leads to a decrease in NOS activity accompanied by an enhancement of nNOS expression in brain mitochondria. At the same time, the activity of mitochondrial enzymatic complexes is markedly diminished. It is suggested an interrelationship between the neurotensinergic and the nitrergic systems. However, the effects of NTS2 activity on mitochondrial bioenergetics are likely to be independent of the regulation of NO synthesis.