Hypoxia increases activity of the BK-channel in the inner mitochondrial membrane and reduces activity of the permeability transition pore.

Abstract

Hypoxia can cause severe damage to cells by initiating signaling cascades that lead to cell death. A cellular oxygen sensor, other than the respiratory chain, might exist in sensitive components of these signaling cascades. Recently, we found evidence that mitochondrial ion channels are sensitive to low levels of oxygen. We therefore studied the effects of hypoxia on the mitochondrial BK-channel (mtBK), on the mitochondrial permeability transition pore (PTP), and on their possible interaction. Using single-channel patch-clamp techniques we found that hypoxia inhibited the PTP but substantially increased the mtBK activity of mitoplasts from rat liver and astrocytes. Experiments measuring the mitochondrial membrane potential of intact rat brain mitochondria (using the fluorescence dye safranine O) during hypoxia exhibited an increased Ca(2+)-retention capacity implying an impaired opening of the PTP. We also found a reduced Ca(2+)-retention capacity with 100 nM iberiotoxin, a selective inhibitor of BK-channels. We therefore conclude that there is interaction between the mtBK and the PTP in a way that an open mtBK keeps the PTP closed. Thus, the response of mitochondrial ion channels to hypoxia could be interpreted as anti-apoptotic.

• Authors: Yu Cheng, Xiang Q Gu, Piotr Bednarczyk, Falk R Wiedemann, Gabriel G Haddad, Detlef Siemen
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 22 Issue 1-4 Pg. 127-36 ( 2008) ISSN: 1421-9778 [Electronic] Germany
• PMID: 18769039 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2008 S. Karger AG, Basel.

Chemical References

• Large-Conductance Calcium-Activated Potassium Channels
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Mitogens
• Peptides
• Solutions
• Dithionite
• iberiotoxin
• Nitrogen

Topics

• Animals
• Cell Hypoxia (drug effects)
• Dithionite (pharmacology)
• Humans
• Ion Channel Gating (drug effects)
• Kinetics
• Large-Conductance Calcium-Activated Potassium Channels (metabolism)
• Membrane Potentials (drug effects)
• Mitochondria, Liver (drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Membranes (drug effects, metabolism)
• Mitochondrial Permeability Transition Pore
• Mitogens (pharmacology)
• Nitrogen (pharmacology)
• Peptides (pharmacology)
• Rats
• Rats, Wistar
• Reproducibility of Results
• Solutions
• Time Factors