Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
Volume 1797, Issue 1, Pages 71-80Publisher
ELSEVIER
DOI: 10.1016/j.bbabio.2009.08.002
Keywords
Mitochondrial volume; Membrane potential; Respiratory control ratio; Valinomycin; P/O ratio; K-Ca activator
Categories
Funding
- NIH [P01HL081427, R37HL54598]
- Novo Nordisk Foundation
- Aase and Ejnar Danielsen Foundation
- Danish Medical Research Council
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R37HL054598, P01HL081427] Funding Source: NIH RePORTER
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Mitochondrial volume regulation depends on K+ movement across the inner membrane and a mitochondrial Ca2+-dependent K+ channel (mitoK(Ca)) reportedly contributes to mitochondrial K+ uniporter activity. Here we utilize a novel K-Ca channel activator, NS11021, to examine the role of mitoK(Ca) in regulating mitochondrial function by measuring K+ flux, membrane potential (Delta psi(m)), light scattering, and respiration in guinea pig heart mitochondria. K+ uptake and the influence of anions were assessed in mitochondria loaded with the K+ sensor PBFI by adding either the chloride (KCl), acetate (KAc), or phosphate (KH2PO4) salts of K+ to energized mitochondria in a sucrose-based medium. K+ fluxes saturated at similar to 10 mM for each salts attaining maximal rates of 172 +/- 17, 54 +/- 2.4, and 33 +/- 3.8 nmol K+/min/mg in KCl, KAc, or KH2PO4, respectively. NS11021 (50 nM) increased the maximal K+ uptake rate by 2.5-fold in the presence of KH2PO4 or KAc and increased mitochondrial volume, with little effect on Delta psi(m). In KCl, NS11021 increased K+ uptake by only 30% and did not increase volume. The effects of NS11021 on K+ uptake were inhibited by the K-Ca toxins charybdotoxin (200 nM) or paxilline (1 mu M). Fifty nanomolar of NS11021 increased the mitochondrial respiratory control ratio (RCR) in KH2PO4, but not in KCl; however, above 1 mu M, NS11021 decreased RCR and depolarized Delta psi(m). A control compound lacking K-Ca activator properties did not increase K+ uptake or volume but had similar nonspecific (toxin-insensitive) effects at high concentrations. The results indicate that activating K+ flux through mitoK(Ca) mediates a beneficial effect on energetics that depends on mitochondrial swelling with maintained Delta psi(m). (C) 2009 Elsevier B.V. All rights reserved.
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