| Autor: |
Balderas E; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT., Lee SHJ; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT., Shankar TS; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT., Yin X; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT., Balynas AM; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT., Kyriakopoulos CP; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT., Selzman CH; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT.; Department of Surgery, Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, UT.; U.T.A.H. (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program: University of Utah Healthcare and School of Medicine, Intermountain Medical Center, Salt Lake Veterans Affairs Health Care System, Salt Lake City, UT., Drakos SG; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT.; U.T.A.H. (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program: University of Utah Healthcare and School of Medicine, Intermountain Medical Center, Salt Lake Veterans Affairs Health Care System, Salt Lake City, UT.; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT., Chaudhuri D; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT.; U.T.A.H. (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program: University of Utah Healthcare and School of Medicine, Intermountain Medical Center, Salt Lake Veterans Affairs Health Care System, Salt Lake City, UT.; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT.; Departments of Biochemistry, Biomedical Engineering, University of Utah, Salt Lake City, UT. |
| Abstrakt: |
Mitochondrial ion channels are essential for energy production and cell survival. To avoid depleting the electrochemical gradient used for ATP synthesis, channels so far described in the mitochondrial inner membrane open only briefly, are highly ion-selective, have restricted tissue distributions, or have small currents. Here, we identify a mitochondrial inner membrane conductance that has strikingly different behavior from previously described channels. It is expressed ubiquitously, and transports cations non-selectively, producing a large, up to nanoampere-level, current. The channel does not lead to inner membrane uncoupling during normal physiology because it only becomes active at depolarized voltages. It is inhibited by external Ca 2+ , corresponding to the intermembrane space, as well as amiloride. This large, ubiquitous, non-selective, amiloride-sensitive (LUNA) current appears most active when expression of the mitochondrial calcium uniporter is minimal, such as in the heart. In this organ, we find that LUNA current magnitude increases two- to threefold in multiple mouse models of injury, an effect also seen in cardiac mitochondria from human patients with heart failure with reduced ejection fraction. Taken together, these features lead us to speculate that LUNA current may arise from an essential protein that acts as a transporter under physiological conditions, but becomes a channel under conditions of mitochondrial stress and depolarization. |
