Reversible Blockade of Electron Transport during Ischemia Protects Mitochondria and Decreases Myocardial Injury following Reperfusion

Chen, Qun; Moghaddas, Shadi; Hoppel, Charles L.; Lesnefsky, Edward J.

doi:10.1124/jpet.106.110262

Cited by 187 publications

(228 citation statements)

References 37 publications

Supporting

Mentioning

206

Contrasting

Order By: Relevance

“…We recently demonstrated that nitrite augments tolerance to I/R injury via the modulation of mitochondrial electron transfer (25). In addition, the inhibition of complex I by nitrite has previously been shown to decrease ROS production by the mitochondria and limit oxidative protein damage (31)(32)(33). Taken together, we here give unequivocal evidence that nitrite modulates mitochondrial function during anoxia and show that this regulation depends on the presence of myoglobin.…”

Section: Discussionsupporting

confidence: 63%

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Hendgen‐Cotta

Merx

Shiva

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

367

353

View full text Add to dashboard Cite

The nitrite anion is reduced to nitric oxide (NO • ) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO • signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ( +/+ ) and knockout ( −/− ) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO • generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO • generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO • by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin +/+ but not in myoglobin −/− hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin +/+ mice, whereas in myoglobin −/− mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation. myoglobin knockout mice

show abstract

Section: Discussionsupporting

confidence: 63%

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Hendgen‐Cotta

Merx

Shiva

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

367

353

View full text Add to dashboard Cite

show abstract

“…As shown previously, partial inhibition of complex I during ischemic incubation would protect mitochondria from damage after reperfusion (42,43). Therefore, it is possible that the reversible deactivation of complex I in the absence of oxygen may function as a protective valve and reduce the burst of respiration downstream of complex I upon tissue reoxygenation.…”

Section: Discussionmentioning

confidence: 97%

Lack of Oxygen Deactivates Mitochondrial Complex I

Galkin

Abramov

Frakich

et al. 2009

Journal of Biological Chemistry

121

126

View full text Add to dashboard Cite

For S-nitrosothiols and peroxynitrite to interfere with the activity of mitochondrial complex I, prior transition of the enzyme from its active (A) to its deactive, dormant (D) state is necessary. We now demonstrate accumulation of the D-form of complex I in human epithelial kidney cells after prolonged hypoxia. Upon reoxygenation after hypoxia there was an initial delay in the return of the respiration rate to normal. This was due to the accumulation of the D-form and its slow, substratedependent reconversion to the A-form. Reconversion to the A-form could be prevented by prolonged incubation with endogenously generated NO. We propose that the hypoxic transition from the A-form to the D-form of complex I may be protective, because it would act to reduce the electron burst and the formation of free radicals during reoxygenation. However, this may become an early pathophysiological event when NO-dependent formation of S-nitrosothiols or peroxynitrite structurally modifies complex I in its D-form and impedes its return to the active state. These observations provide a mechanism to account for the severe cell injury that follows hypoxia and reoxygenation when accompanied by NO generation.The mechanisms underlying the cellular response to hypoxia and their consequences are not completely understood. Because the mitochondrial respiratory chain is the major consumer of oxygen, mitochondria are likely to play a significant role in regulating its distribution in cells and tissues (1). Cells have the ability to decrease oxygen demand at low [O 2 ] (2, 3), and the affinity of cytochrome c oxidase for oxygen is considered to be the most important factor in the decrease of mitochondrial oxygen consumption during hypoxia (4, 5). The interaction of nitric oxide (NO) 2 with cytochrome c oxidase has been shown to be a significant determinant of the affinity of this enzyme for oxygen and is responsible for reducing cellular consumption of oxygen at low [O 2 ]. Nitric oxide also plays a role in the early reduction of mitochondrial cytochromes that occurs as the [O 2 ] decreases (6, 7). A direct consequence of such reduction is a backlog of electrons at all the redox centers of the respiratory chain, including cytochromes and ubiquinone, as well as the intramitochondrial pool of NAD(P)H.Mitochondrial complex I (EC 1.6.5.3, proton-translocating NADH:ubiquinone oxidoreductase) is responsible for oxidation of matrix NADH by membrane-bound ubiquinone and is the major entry point for electrons to the respiratory chain (8). It is also a major source of mitochondrial reactive oxygen species (ROS) (9 -11). Two catalytically and structurally distinct forms of complex I have been identified in partially purified preparations in vitro: one is a fully competent, "active" A-form, and the other is a dormant, silent, "deactivated" D-form (12). In such systems a so-called pseudo-reversible A/D transition has been described in mammalian and other vertebrate complex I (13). The turnover number of active complex I in submitochondrial particles (SM...

show abstract

“…Another possible mechanism for H 2 S protective action on mitochondrial function may lie in its ability to modulate cellular respiration during reperfusion. The inhibition of mitochondrial respiration has been shown (26,27) to protect against MI-R injury by limiting the generation of reactive oxygen species and diminishing the degree of mitochondrial uncoupling leading to decreased infarct size and preserved function. The accumulation of evidence that mitochondrial function and structure was preserved after myocardial infarction in mice treated with H 2 S was further corroborated by the decreased activation of caspase-3 and a decrease in the number of TUNEL positive nuclei, suggesting that H 2 S was capable of inhibiting the progression of apoptosis after MI-R injury.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function

Elrod¹,

Calvert²,

Morrison

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

1,022

892

View full text Add to dashboard Cite

The recent discovery that hydrogen sulfide (H2S) is an endogenously produced gaseous second messenger capable of modulating many physiological processes, much like nitric oxide, prompted us to investigate the potential of H2S as a cardioprotective agent. In the current study, we demonstrate that the delivery of H2S at the time of reperfusion limits infarct size and preserves left ventricular (LV) function in an in vivo model of myocardial ischemiareperfusion (MI-R). This observed cytoprotection is associated with an inhibition of myocardial inflammation and a preservation of both mitochondrial structure and function after I-R injury. Additionally, we show that modulation of endogenously produced H2S by cardiac-specific overexpression of cystathionine ␥-lyase (␣-MHC-CGL-Tg mouse) significantly limits the extent of injury. These findings demonstrate that H2S may be of value in cytoprotection during the evolution of myocardial infarction and that either administration of H2S or the modulation of endogenous production may be of clinical benefit in ischemic disorders.

show abstract

Reversible Blockade of Electron Transport during Ischemia Protects Mitochondria and Decreases Myocardial Injury following Reperfusion

Cited by 187 publications

References 37 publications

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Lack of Oxygen Deactivates Mitochondrial Complex I

Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function

Contact Info

Product

Resources

About