Regulation of the Human Cardiac Mitochondrial Ca2+Uptake by 2 Different Voltage-Gated Ca2+Channels

• DOI: 10.1161/circulationaha.108.835389
• Publication Date: 2009-04-28T01:49:50Z
• Authors: Guido Michels; Ismail F. Khan; Jeannette Endres-...; Dennis Rottlaender; Stefan Herzig; Arjang Ruhparwar; Thorsten Wahlers; Uta C. Hoppe
• Keywords: Cardiomyopathy, Dilated; Heart Failure; 0301 basic medicine; Patch-Clamp Techniques; Biophysics; Myocardial Ischemia; In Vitro Techniques; Ruthenium Red; Mitochondria; Kinetics; 03 medical and health sciences; Humans; Calcium; Indicators and Reagents; Myocytes, Cardiac; Calcium Channels; Ion Channel Gating

Background— Impairment of intracellular Ca 2+ homeostasis and mitochondrial function has been implicated in the development cardiomyopathy. Mitochondrial uptake is thought to be mediated by uniporter (MCU) a thus far speculative non-MCU pathway. However, identity properties these pathways are matter intense debate, possible functional alterations diseased states have remained elusive. Methods Results— By patch clamping inner membrane mitochondria from nonfailing failing human hearts, we identified 2 previously unknown -selective channels, referred as mCa1 mCa2. Both channels voltage dependent but differ significantly gating parameters. Compared with mCa2 exhibit higher single-channel amplitude, shorter openings, lower open probability, 3 5 subconductance states. Similar MCU, inhibited 200 nmol/L ruthenium 360, whereas insensitive 360 reduced only very high concentrations (10 μmol/L). unaffected blockers other possibly -conducting pores were activated spermine (1 mmol/L). Notably, activity decreased compared heart conditions, making them less effective for likely -induced metabolism. Conclusions— Thus, conclude that distinct which functionally impaired failure. Current reveal channel underlies MCU responsible red–insensitive/low-sensitivity non-MCU–type uptake.