The presence of
nitric oxide (NO* ) in the mitochondria led to analysis of its source and functions in mitochondrial homeostasis. Studies have revealed the existence of a mtNOS
isoform with similar features to nNOS, with some post-traslational modifications, although without the typical
signal peptide responsible for addressing
proteins to mitochondrion. This
isoform may account for the physiological production of NO* related to the respiratory control. During inflammatory conditions there is an excess of NO* in the mitochondria responsible for an increase in reactive
oxygen and
nitrogen species in sufficient amounts to compromise mitochondrial function. These conditions led to the discovery of the presence of an inducible mtNOS
isoform with kinetic properties similar to iNOS. Experiments with knockout mice lacking either nNOS or iNOS further confirmed the existence of these two mtNOS
isoforms in mitochondria. Although the increase in NO* in
sepsis by inducible mtNOS may have important regulatory functions including the redistribution of
oxygen into other pathways under
hypoxia, it causes the production of excess NO* that is deleterious for the cell.
Melatonin, an
endogenous antioxidant, regulates mitochondrial respiration and bioenergetics and protects mitochondria from excess NO* by controlling the activity of mtNOS.