Israel Sekler - Curriculum Vitae#

Education

• The Hebrew University of Jerusalem, Faculty of Agriculture, Israel BSc 1981 - 1984 Animal Physiology
  
• Weizmann Institute of Science, Israel MSc 1984 - 1986 Chemical Immunology
  
• Weizmann Institute of Science, Israel PhD 1987 - 1992 Biochemistry
  
• Stanford University, USA Postdoctoral 1992 - 1996 Physiology

Research

My research is focused on calcium and zinc homeostasis. The mitochondrial Na+/Ca2+ exchanger, is a key player in mitochondrial and cellular calcium homeostasis but although its existence was documented 40 years ago its molecular identity remained unknown until now. 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 which we are currently pursuing. Another recent project conducted in my lab is termed optometabolic control. This project was recently awarded with the highly prestigious DIP grant. In this project we take advantage of our ability to target light activated proton channels into the inner membrane of the mitochondria. Activation of these channels by light triggers fast light dependent and reversible control of mitochondrial membrane potential and control ATP production and mitochondrial Ca2+ shuttling. Because these “optometabolic” constructs are precisely tunable in time and space, and expressed selectively in the mitochondrial they will provide the first molecular “switch” to control the mitochondrial metabolism.

Positions and Honors

• 2014 - present President of the Israeli society for Physiology and Pharmacology
  
• 2011 - present Full Professor, Department of Physiology, and Cell Biology Faculty of Health Sciences, Ben-Gurion University of the Negev
  
• 2011 - 2015 Chairman Department of Physiology, and Cell Biology Faculty of Health Sciences
  
• 2008 - 2011 Associate Professor, Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev
  
• 2003 - 2008 Senior Lecturer, Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev. Tenured at 2004.
  
• 1998 - 2003 Lecturer, Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev
  
• 1996 - 1998 Kreitman Fellow, Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev

Contributions to Science

1) Identification of the mitochondrial calcium exchanger NCLX

We identified the mitochondrial Na+/Ca2+ exchanger. This transporter is the major Ca2+ extruder in mitochondria

2) The physiological role of NCLX

A major caveat in the field of mitochondrial Ca2+ signaling was non-selectivity of the common inhibitors of the Ca2+ uniporter and the exchanger. The molecular identification of the mitochondrial exchanger facilitated for the first time an in depth analysis of its physiological function. Using dominant negative and siRNA strategy, we studied the role of this exchanger. We found that it is critical for Ca2+ signaling in astrocytes. Knockdown of the exchanger expression also a profound effect on the pattern of insulin secretion from beta-cells. Our studies also indicate that mitochondrial Ca2+ signaling controlled by NCLX is essential for pain sensation by DRG neurons.

3) The regulation of NCLX its cellular effectors

The molecular handle provided by the cloning of NCLX enabled for the first time the identification of its regulatory domains. We found that NCLX is strongly regulated by the PKA pathway. We found that it is mediated by a phosphorylation by PKA of a serine residue on its regulatory domain. This mode of regulation was essential to protect dopaminergic neurons affected by the PINK1 PD-associated mutation. We further found that the activity of NCLX controls the redox state of mitochondria and thereby is regulating the major cell membrane Ca2+ signaling player. The store-operated Ca2+ channel.

Ongoing Research Support

2014-2017 ISF-China PI: Sekler, Novel signaling pathway between the acid sensing channel ASIC1a and the mitochondrial Na+/Ca2+ exchanger NCLX control neuronal fate in ischemia.

2014-2019 DIP: PI: Sekler, Optometabolic and molecular analysis of functional links between mitochondrial Ca2+ signaling, gene regulation and metabolism in the brain.

2017-2021: ISF PI: Sekler, Physiological implications of mitochondrial Na+/Ca2+ exchanger (NCLX) regulation by membrane potential and phosphorylation.