Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels.
BACKGROUND
Impairment of intracellular Ca(2+) homeostasis and mitochondrial function has been implicated in the development of cardiomyopathy. Mitochondrial Ca(2+) uptake is thought to be mediated by the Ca(2+) uniporter (MCU) and a thus far speculative non-MCU pathway. However, the identity and properties of these pathways are a matter of intense debate, and possible functional alterations in diseased states have remained elusive.


RESULTS
By patch clamping the inner membrane of mitochondria from nonfailing and failing human hearts, we have identified 2 previously unknown Ca(2+)-selective channels, referred to as mCa1 and mCa2. Both channels are voltage dependent but differ significantly in gating parameters. Compared with mCa2 channels, mCa1 channels exhibit a higher single-channel amplitude, shorter openings, a lower open probability, and 3 to 5 subconductance states. Similar to the MCU, mCa1 is inhibited by 200 nmol/L ruthenium 360, whereas mCa2 is insensitive to 200 nmol/L ruthenium 360 and reduced only by very high concentrations (10 micromol/L). Both mitochondrial Ca(2+) channels are unaffected by blockers of other possibly Ca(2+)-conducting mitochondrial pores but were activated by spermine (1 mmol/L). Notably, activity of mCa1 and mCa2 channels is decreased in failing compared with nonfailing heart conditions, making them less effective for Ca(2+) uptake and likely Ca(2+)-induced metabolism.


CONCLUSIONS
Thus, we conclude that the human mitochondrial Ca(2+) uptake is mediated by these 2 distinct Ca(2+) channels, which are functionally impaired in heart failure. Current properties reveal that the mCa1 channel underlies the human MCU and that the mCa2 channel is responsible for the ruthenium red-insensitive/low-sensitivity non-MCU-type mitochondrial Ca(2+) uptake.
Michels
Guido
G
Department of Internal Medicine III, University of Cologne, Cologne, Germany.
Khan
Ismail F
IF
Endres-Becker
Jeannette
J
Rottlaender
Dennis
D
Herzig
Stefan
S
Ruhparwar
Arjang
A
Wahlers
Thorsten
T
Hoppe
Uta C
UC
D001703:Biophysics; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000145:classification / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008928:Mitochondria / Q000502:physiology*; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D012430:Ruthenium Red / Q000494:pharmacology
D015220:Calcium Channels; D007202:Indicators and Reagents; C034703:mitochondrial calcium uniporter; D012430:Ruthenium Red; D002118:Calcium