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

G Michels, IF Khan, J Endres-Becker, D Rottlaender… - Circulation, 2009 - Am Heart Assoc
G Michels, IF Khan, J Endres-Becker, D Rottlaender, S Herzig, A Ruhparwar, T Wahlers
Circulation, 2009Am Heart Assoc
Background—Impairment of intracellular Ca2+ homeostasis and mitochondrial function has
been implicated in the development of cardiomyopathy. Mitochondrial Ca2+ uptake is
thought to be mediated by the Ca2+ 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.
Methods and Results—By patch clamping the inner membrane of mitochondria from …
Background— Impairment of intracellular Ca2+ homeostasis and mitochondrial function has been implicated in the development of cardiomyopathy. Mitochondrial Ca2+ uptake is thought to be mediated by the Ca2+ 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.
Methods and Results— By patch clamping the inner membrane of mitochondria from nonfailing and failing human hearts, we have identified 2 previously unknown Ca2+-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 μmol/L). Both mitochondrial Ca2+ channels are unaffected by blockers of other possibly Ca2+-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 Ca2+ uptake and likely Ca2+-induced metabolism.
Conclusions— Thus, we conclude that the human mitochondrial Ca2+ uptake is mediated by these 2 distinct Ca2+ 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 Ca2+ uptake.
Am Heart Assoc