In:
American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 292, No. 1 ( 2007-01), p. C148-C156
Abstract:
We recently demonstrated a role for altered mitochondrial bioenergetics and reactive oxygen species (ROS) production in mitochondrial Ca 2+ -sensitive K + (mtK Ca ) channel opening-induced preconditioning in isolated hearts. However, the underlying mitochondrial mechanism by which mtK Ca channel opening causes ROS production to trigger preconditioning is unknown. We hypothesized that submaximal mitochondrial K + influx causes ROS production as a result of enhanced electron flow at a fully charged membrane potential (ΔΨ m ). To test this hypothesis, we measured effects of NS-1619, a putative mtK Ca channel opener, and valinomycin, a K + ionophore, on mitochondrial respiration, ΔΨ m , and ROS generation in guinea pig heart mitochondria. NS-1619 (30 μM) increased state 2 and 4 respiration by 5.2 ± 0.9 and 7.3 ± 0.9 nmol O 2 ·min −1 ·mg protein −1 , respectively, with the NADH-linked substrate pyruvate and by 7.5 ± 1.4 and 11.6 ± 2.9 nmol O 2 ·min −1 ·mg protein −1 , respectively, with the FADH 2 -linked substrate succinate (+ rotenone); these effects were abolished by the mtK Ca channel blocker paxilline. ΔΨ m was not decreased by 10–30 μM NS-1619 with either substrate, but H 2 O 2 release was increased by 44.8% (65.9 ± 2.7% by 30 μM NS-1619 vs. 21.1 ± 3.8% for time controls) with succinate + rotenone. In contrast, NS-1619 did not increase H 2 O 2 release with pyruvate. Similar results were found for lower concentrations of valinomycin. The increase in ROS production in succinate + rotenone-supported mitochondria resulted from a fully maintained ΔΨ m , despite increased respiration, a condition that is capable of allowing increased electron leak. We propose that mild matrix K + influx during states 2 and 4 increases mitochondrial respiration while maintaining ΔΨ m ; this allows singlet electron uptake by O 2 and ROS generation.
Type of Medium:
Online Resource
ISSN:
0363-6143
,
1522-1563
DOI:
10.1152/ajpcell.00215.2006
Language:
English
Publisher:
American Physiological Society
Publication Date:
2007
detail.hit.zdb_id:
1477334-X
detail.hit.zdb_id:
392098-7
SSG:
12
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