Current Research
Mitochondrial Ca2+ signaling
The mitochondrial Na+/Ca2+ exchanger (NCLX) is a key player in mitochondrial and cellular calcium homeostasis. Although its existence was documented some 40 years ago, its molecular identity has remained elusive. By combining molecular silencing, ectopic expression and dominant negative analysis with imaging of mitochondrial and cellular calcium levels, we have identified NCLX as the long-sought exchanger. This finding opens the door to molecular analysis of the mitochondrial Ca2+ transport machinery and physiological studies ranging from cardiac activity to insulin secretion and neuronal activity. Based on an examination of human mutations of NCLX, we are now linking mitochondrial signaling to major human maladies ranging from diabetes to Parkinson’s disease, Alzheimer’s disease and stroke. Furthermore, by combing molecular modeling with appropriate screens for potential NCLX agonists and antagonists, we plan to identify novel drugs that might interrupt these major health syndromes and presently unmet clinical needs.Opto-metabolic control Metabolic activity not only controls the life and death of cells but is also linked to major diseases when impaired. Although we can readily monitor metabolic activity, we cannot selectivity control such processes because currently available reagents are devoid of selectivity and often act as irreversible metabolic poisons. In our laboratory, we are focusing on a novel strategy termed opto-metabolic control. Our aim is to target light-dependent molecular switches into mitochondria, thereby controlling metabolic activity in cells both selectively and in a temporally controlled manner. This strategy will provide global molecular control of metabolic activities in sub-cellular fractions, cells, tissues and organs.
Heavy metals in health and disease
Zinc is an essential micronutrient required for growth and development yet is strikingly similar to cadmium, a highly toxic environmental pollutant. Indeed, due to their similarity, zinc transporters can be hijacked by cadmium, thus gaining access into the body. Indeed, the similarity of the two metals is so remarkable that there are no chelators that can distinguish between the two. By combing molecular modeling with functional assays, we have identified the first mammalian transporter and ion binding site that can transport zinc yet reject cadmium. Our current efforts are focused on identifying the functional mechanism(s) of this and other zinc transporters, as well as the molecular basis for heavy metal selectivity.
Selected publications
Palty R., Ohana E., Hershfinkel M., Volokita M., Elgazar V., Beharier O., Silverman W.F., Argaman M. and Sekler I. (2004). Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger. J. Biol. Chem. 279: 25234-25240.
Palty R., Silverman W.F., Hershfinkel M., Caporale T., Sensi S.L., Parnis J., Nolte C., Fishman D., Shoshan-Barmatz V., Herrmann S., Khananshvili D. and Sekler I. (2010). NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. PNAS 107:436-441.
Nita I.I., Hershfinkel M., Fishman D., Ozeri E., Rutter G.A., Sensi S.L., Khananshvili D., Lewis E.C. and Sekler I. (2012). The mitochondrial Na(+)/Ca(2+) exchanger upregulates glucose dependent Ca(2+) signaling linked to insulin secretion. PLoS One 7(10):e46649.
Hoch E., Lin W., Chai J., Hershfinkel M., Fu D. and Sekler I. (2012). Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity. Proc. Natl. Acad. Sci. U.S.A. 109(19):7202-7207.
Parnis J., Montana V., Delgado-Martinez I., Matyash V., Parpura V., Kettenmann H., Sekler I. and Nolte C. (2013). Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes. J. Neurosci. 33(17):7206-7219.
