Synchronized Whole Cell Oscillations in Mitochondrial Metabolism Triggered by a Local Release of Reactive Oxygen Species in Cardiac Myocytes
Open accessAbstract
Reactive oxygen species (ROS) and/or Ca2+ overload can trigger depolarization of mitochondrial inner membrane potential (DeltaPsim) and cell injury. Little is known about how loss of DeltaPsim in a small number of mitochondria might influence the overall function of the cell. Here we employ the narrow focal excitation volume of the two-photon microscope to examine the effect of local mitochondrial depolarization in guinea pig ventricular myocytes. Remarkably, a single local laser flash triggered synchronized and self-sustained oscillations in DeltaPsim, NADH, and ROS after a delay of approximately 40s, in more than 70% of the mitochondrial population. Oscillations were initiated only after a specific threshold level of mitochondrially produced ROS was exceeded, and did not involve the classical permeability transition pore or intracellular Ca2+ overload. The synchronized transitions were abolished by several respiratory inhibitors or a superoxide dismutase mimetic. Anion channel inhibitors potentiated matrix ROS accumulation in the flashed region, but blocked propagation to the rest of the myocyte, suggesting that an inner membrane, superoxide-permeable, anion channel opens in response to free radicals. The transitions in mitochondrial energetics were tightly coupled to activation of sarcolemmal KATP currents, causing oscillations in action potential duration, and thus might contribute to catastrophic arrhythmias during ischemia-reperfusion injury.
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In the absence of rotenone, NAD+-linked substrates can also enhance O2•- generation at complex I if the ΔΨm is higher than normal.
“In the absence of rotenone, NAD+-linked substrates can also enhance O2•- generation at complex I if the ΔΨm is higher than normal (8)”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [8]
Cytochrome c may function to shunt any free electrons released outside the matrix to complex IV, thus initially reducing O2•− generation.
“and cytochrome c may function to shunt any free electrons released outside the matrix to complex IV, thus initially reducing O2•− generation (8).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [8]
The overabundance of ROS during Ca2+ overload with a collapsed ΔΨm could reflect more the inability of the GSH, Pr-SSG, and TRXSH2 systems to regenerate the reduced state than of more ROS to be generated.
“The overabundance of ROS during Ca2+ overload with a collapsed ΔΨm could reflect more the inability of the GSH, Pr-SSG, and TRXSH2 systems to regenerate the reduced state (thus less H2O2 removal) than of more ROS to be generated (8).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [8]
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- Authors
- Aon, M. A., Cortassa, S., Marbán, E., & O'Rourke, B.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- O'Rourke, Brian
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 278
- Issue
- 45
- Pages
- 44735-44744
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2015221597
- Cited by
- 521
- References
- 58
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 10 · 2023: 19 · 2022: 14 · 2021: 19 · 2020: 17 · 2019: 18 · 2018: 18 · 2017: 24 · 2016: 27 · 2015: 24 · 2014: 41 · 2013: 37 · 2012: 31
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R37 HL-36957, R01HL054598, R37HL036957, R01HL54598)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- mitochondrial oscillations, reactive oxygen species, mitochondrial depolarization, cardiomyocytes, NADH, superoxide, anion channels, ATP-sensitive potassium channels, action potential duration, ischemia-reperfusion arrhythmia, mitochondrial metabolism, two-photon excitation, superoxide dismutase
- MeSH terms
- Action Potentials, Animals, Anions, Calcium, Cell Membrane Permeability, Electric Conductivity, Energy Metabolism, Guinea Pigs, Intracellular Membranes, Ion Channels, Membrane Potentials, Mitochondria, Heart, NAD, Periodicity, Sarcolemma, Reactive Oxygen Species, Myocytes, Cardiac
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