University of Vermont (P30 GM103498)
"Center for Neuroscience Excellence"
Pilot Project 4: "Mitochondrial Dysfunction and Asynchronous Release in Diabetic Mice"
Investigator: John Tompkins, Ph.D.
Diabetes can profoundly disrupt autonomic coordination of visceral organ function. Urogenital, gastrointestinal and cardiovascular systems are compromised, producing erectile dysfunction, bladder dysfunction, gastroparesis, constipation, postural hypotension, arrhythmias and sudden cardiac death. In an effort to elucidate the cellular mechanisms underlying the loss of autonomic control, I recently determined that type 2 diabetes alters neurotransmitter release from parasympathetic nerve terminals of the major pelvic ganglion (MPG). This alteration was evident as a significant increase in asynchronous neurotransmitter release both during and after tetanic stimulation. The purpose of this application is to determine whether the increased asynchronous release is a measure of mitochondrial dysfunction with diabetes.
Nerve terminal mitochondria play an important role in buffering the transient rise in [Ca2+]i during repetitive stimulation of motor nerves. Inhibition of mitochondrial function, at the motor endplate, causes greater asynchronous release. Both type 1 and type 2 diabetes are known to disrupt mitochondrial bioenergetics as a consequence of the over abundance of oxidative substrates. It has not yet been determined whether a loss of mitochondrial function with diabetes disrupts Ca2+ homeostasis at autonomic nerve terminals. The objective in this application is to determine if compromised mitochondrial function causes the increased asynchronous release observed in type 2 diabetic mice. My hypothesis is that type 2 diabetes decreases mitochondrial sequestration of nerve terminal Ca2+ during tetanic stimulation causing greater asynchronous neurotransmitter release. This hypothesis is formulated, in part, based on the existing literature and my preliminary data demonstrating that depolarization of the mitochondrial membrane potential (Δψm) with the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) also increases asynchronous release at MPG preganglionic nerve terminals.