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Cited by 50Mitochondrial Function and PathologyIon channel regulation and functionCardiac Ischemia and Reperfusion

Pharmacological and physiological stimuli do not promote Ca2+-sensitive K+channel activity in isolated heart mitochondria

Cancherini, Douglas V., Queliconi, Bruno B., Kowaltowski, Alicia J.·2007·Cardiovascular Research
DOI 10.1016/j.cardiores.2006.11.035
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Abstract

OBJECTIVE: Mitochondrial calcium-activated K(+) (mitoK(Ca)) channels have been described as channels that are activated by Ca(2+), inner mitochondrial membrane depolarization and drugs such as NS-1619. NS-1619 is cardioprotective, leading to the assumption that this effect is related to the opening of mitoK(Ca) channels. Here, we show several weaknesses in this hypothesis. METHODS: Isolated mitochondria from rat hearts were tested for evidence of mitoK(Ca) activity by analyzing functional parameters in K(+)-rich and K(+)-free media. RESULTS: NS-1619 promoted mitochondrial depolarization both in K(+)-rich and K(+)-free media. Respiratory rate increments were also seen in the presence of NS-1619 for both media. In parallel, NS-1619 promoted respiratory inhibition, as evidenced by respiratory measurements in state 3. Mitochondrial volume measurements conducted using light scattering showed that NS-1619 led to swelling, in a manner unaltered by inhibitors of mitoK(Ca) channels, antagonists of adenosine triphosphate-sensitive potassium channels or inhibitors of the permeability transition. Swelling was also maintained when K(+) in the media was substituted with tetraethylammonium (TEA(+)), which is not transported by any known K(+) carrier. Electron microscopy experiments gave support to the idea that NS-1619-induced mitochondrial swelling took place in the absence of K(+). In addition to testing the pharmacological effects of NS-1619, we attempted, unsuccessfully, to promote mitoK(Ca) activity by altering Ca(2+) concentrations in the medium and inducing mitochondrial uncoupling. CONCLUSION: Our data indicate that NS-1619 promotes non-selective permeabilization of the inner mitochondrial membrane to ions, in addition to partial respiratory inhibition. Furthermore, we found no specific K(+) transport in isolated heart mitochondria compatible with mitoK(Ca) opening, whether by pharmacological or physiological stimuli. Our results indicate that NS-1619 has extensive mitochondrial effects unrelated to mitoK(Ca) and suggest that tissue protection mediated by NS-1619 may occur through mechanisms other than activation of these channels.

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Authors
Cancherini, D. V., Queliconi, B. B., & Kowaltowski, A. J.
Affiliations
Universidade de São Paulo (BR)
Corresponding author
Kowaltowski, Alicia J.
ORCID
Venue
Cardiovascular Research
Publisher
Oxford University Press (OUP)
Published
2007-03-01
Volume
73
Issue
4
Pages
720-728
ISSN
  • 0008-6363 (ISSN-L)
  • 1755-3245
DOI
10.1016/j.cardiores.2006.11.035
OpenAlex
W2168568807
Cited by
50
References
45
Citations by year
2024: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 1 · 2012: 3
FWCI
1.90
Type
journal article
Language
en
Open access
closed
Locations
  • Cardiovascular Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
Keywords
NS1619, mitochondrial depolarization, mitochondrial swelling, respiratory inhibition, tetraethylammonium, potassium transport, cardioprotection, mitochondrial permeability transition, mitochondrial uncoupling
MeSH terms
Animals, Benzimidazoles, Calcium, Culture Media, Malates, Membrane Potentials, Microscopy, Fluorescence, Mitochondria, Heart, Mitochondrial Swelling, NADP, Oligomycins, Oxidation-Reduction, Oxygen Consumption, Phenazines, Potassium, Rotenone, Sodium, Uncoupling Agents, Ion Channel Gating, Rats, Sprague-Dawley, Glutamic Acid, Tetraethylammonium, Succinic Acid, Potassium Channels, Calcium-Activated, Tissue Culture Techniques, Microscopy, Electron, Transmission, Mitochondrial Membranes, Rats

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