The role of
mitochondrial dysfunction in alterations of
calcium signalling in primary sensory neurons has been studied in mice with
streptozotocin-induced and genetically predisposed
diabetes mellitus before and after additional treatment with
insulin infusions. Cytosolic
calcium transients triggered by membrane depolarization were measured using a membrane-permeable form of fluorescent
indicator indo-1, and their changes after application of mitochondrial uncoupler
carbonyl cyanide m-chlorphenylhydrazone were compared in cells of control and diabetic animals. Considerable prolongation of residual elevation of cytosolic
calcium after termination of membrane depolarization was observed in diabetic mice, which was expressed mainly in small-sized (nociceptive) neurons. This correlated with the level of
hyperglycemia, which was maximal in cells from
streptozotocin-treated mice.
Insulin partly reversed these changes.
Carbonyl cyanide m-chlorophenylhydrazone application to neurons of control mice enlarged the peak of
calcium transients and decreased residual
calcium elevations, indicating that mitochondria in physiological conditions participate in shaping of these transients by diminishing their peak due to rapid uptake of
calcium ions and by prolonging them due to subsequent slow
calcium release back into the cytosol. Depression of the
calcium accumulating function of mitochondria by
carbonyl cyanide m-chlorophenylhydrazone eliminated these changes. The prolonged residual elevation of cytosolic
calcium characteristic for neurons of diabetic animals was also eliminated by
carbonyl cyanide m-chlorophenylhydrazone, confirming the suggestion that such elevation is determined mainly by
mitochondrial dysfunction, the latter being dependent on the level of
hyperglycemia. Predominant expression of such changes in small-sized neurons can be explained by the absence in them of effective
calcium-buffering by the endoplasmic reticulum. Possible role of the described
calcium signalling changes in the origin of neuropathic syndromes is discussed.