Our research focuses on establishing the molecular identity of intracellular ion channels and elucidates their targeting mechanism and biophysical properties. At the functional level, we focus on how organellar ion channels regulate cellular physiology by altering mitochondrial properties. To understand their role in health and disease, our group is focused on their role in cardiac (dys) function in the aging heart. The current projects are:
Molecular identity and regulation of mitochondrial ion channels
The Singh lab at OSU is focused on elucidating the molecular identity of mitochondrial ion channels, their localization in mitochondria, and how they are translocated to the mitochondria. The group has established that cardiac BKca channels are splice variants of BKca. Recently, the group has established that CLIC5 is present in the inner membrane of cardiac mitochondria and CLIC4 is present ‘preferentially’ in the outer membrane of cardiac mitochondria. The critical question after establishing the molecular identity is to test whether these proteins do ‘work’ like ion channels. The group is now focused on the biophysical properties of these newly discovered channels, and how changes in the mitochondrial environment modulate the channel activity.
Ion Channels in Extracellular Vesicles (EVs)
We have recently discovered ion channels in EVs and obtained their functional relevance. The group is focused on understanding the role of EV ion channels in maintaining the integrity and content of EVs. We are incorporating novel electrophysiology and imaging techniques.
Regulation of mitochondrial structure and function by mitochondrial ion channels
If ion channels are present in mitochondria, the next important question is what are they doing in mitochondria? Do they affect the mitochondrial structure, fission and/or fusion, and physiological properties of mitochondria? To understand physiology, physiological outcomes of pharmacological (activation and blocking) and genetic (knock out and gain of function) interventions at isolated mitochondrial and cellular levels are measured. The lab has access to animal models (flies and transgenic mice) and fresh human tissues from the OSU tissue donor program.
Role of mitochondrial ion channels in cardioprotection from ischemia-reperfusion injury
Cardiac or myocardial ischemia occurs when blood flow to the heart is reduced or stopped which results in a decrease in the supply of oxygen to the heart tissue. If myocardial ischemia is not checked immediately, it results in myocardial infarction. Even if the blood supply is restored, it does result in significant myocardial infarction due to reperfusion. Ion channels present in mitochondria were shown to be protective on activation from ischemia and reperfusion injury. The group has earlier shown that NS1619 (BKca activator) protects the wild-type heart but not the BKca null mutant heart. The group is focused on how mitochondrial ion channels regulate mitochondrial as well as cellular physiology to minimize myocardial infarction.
Role of mitochondrial ion channels in the regulation of cardiac function and aging
With improved health care and the availability of nutrition, the average age of the human population is increasing. An increase in average age is associated with a progressive decline in several physiological processes such as cardiovascular function. Age increases susceptibility to myocardial infarction, cardiac hypertrophy, and heart failure. The Singh lab in collaboration with Dr. Gururaja Rao’s group studies how mitochondrial ion channels affect the function and susceptibility to myocardial infarction and heart attack of the aging heart. Mice and Drosophila models are used to study aging and cardiac function/ dysfunction.