Decrease in Mitochondrial Complex I Activity in Ischemic/Reperfused Rat Heart

Paradies, Giuseppe; Petrosillo, Giuseppe; Pistolese, Marilva; Venosa, Nicola Di; Federici, Antonio; Ruggiero, Francesca

doi:10.1161/01.res.0000109416.56608.64

Cited by 410 publications

(294 citation statements)

References 56 publications

Supporting

Mentioning

268

Contrasting

Unclassified

Order By: Relevance

“…43 However, neither increased peroxide production, oxidative damage to proteins or lipids, nor elevation of oxidative stress defense mechanisms were found, with the exception of increased immunocytochemical staining of MnSOD. We do not have a clear-cut explanation for these discrepant results, but in the absence of any other indication for the development of reactive oxygen species, we hypothesize that the increased staining of MnSOD is not directly involved in an oxidative stress response.…”

Section: Discussionmentioning

confidence: 94%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

et al. 2005

View full text Add to dashboard Cite

Peroxisome deficiency in men causes severe pathology in several organs, particularly in the brain and liver, but it is still unknown how metabolic abnormalities trigger these defects. In the present study, a mouse model with hepatocyte-selective elimination of peroxisomes was generated by inbreeding Pex5-loxP and albumin-Cre mice to investigate the consequences of peroxisome deletion on the functioning of hepatocytes. Besides the absence of catalase-positive peroxisomes, multiple ultrastructural alterations were noticed, including hepatocyte hypertrophy and hyperplasia, smooth endoplasmic reticulum proliferation, and accumulation of lipid droplets and lysosomes. Most prominent was the abnormal structure of the inner mitochondrial membrane, which bore some similarities with changes observed in Zellweger patients. This was accompanied by severely reduced activities of complex I, III, and V and a collapse of the mitochondrial inner membrane potential. Surprisingly, these abnormalities provoked no significant disturbances of adenosine triphosphate (ATP) levels and redox state of the liver. However, a compensatory increase of glycolysis as an alternative source of ATP and mitochondrial proliferation were observed. No evidence of oxidative damage to proteins or lipids nor elevation of oxidative stress defence mechanisms were found. Altered expression of peroxisome proliferator-activated receptor alpha (PPAR-␣) regulated genes indicated that PPAR-␣ is activated in the peroxisomedeficient cells. In conclusion, the absence of peroxisomes from mouse hepatocytes has an impact on several other subcellular compartments and metabolic pathways but is not detrimental to the function of the liver parenchyma. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). P eroxisomes are indispensable in cellular metabolism, because they harbor enzymes essential for the degradation of very long chain and branched chain fatty acids, for the conversion of cholesterol in bile acids and for the synthesis of ether phospholipids and polyunsaturated fatty acids. They also participate in the catabolism of purines, polyamines, and pipecolic acid. 1 The importance of peroxisomes is stressed by the existence of a group of genetic disorders in which one or more peroxisomal functions are impaired. The most severe is the cerebrohepatorenal syndrome of Zellweger, a peroxisome assembly disorder characterized by the absence of functional peroxisomes due to a disturbance in the peroxisomal protein import machinery. 2 At birth, Zellweger syndrome patients suffer from neurological and eye abnormalities, hypotonia, characteristic craniofacial dysmorphism, and renal cysts. 2 Hepatic pathology develops in the postnatal period, including hepatomegaly, fibrosis, micronodular cirrhosis, cholestasis, hyperbilirubinemia, and elevation of aminotransferases. 2,3 The biochemical hallmarks of this syndrome include the accumulation of very long chain and branched chain fatty aci...

show abstract

Section: Discussionmentioning

confidence: 94%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Ischemia/reperfusion-induced oxidative stress has a noticeable influence on NADH-ubiquinone reductase (complex I) activity, since it transitorily diminishes it (Paradies et al 2004). Complex II activity is also robustly reduced by reperfusion-induced oxidative stress (Pasdois et al 2006;Chen et al 2008) via deglutathionylation of its 70-kDa flavin protein and tyrosine nitration by peroxynitrite (Chen et al 2007(Chen et al , 2008.…”

Section: Introductionmentioning

confidence: 99%

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Mourmoura

Leguen

Dubouchaud

et al. 2010

AGE

View full text Add to dashboard Cite

Aging compromises restoration of the cardiac mechanical function during reperfusion. We hypothesized that this was due to an ampler release of mitochondrial reactive oxygen species (ROS). This study aimed at characterising ex vivo the mitochondrial ROS release during reperfusion in isolated perfused hearts of middle-aged rats. Causes and consequences on myocardial function of the observed changes were then evaluated. The hearts of rats aged 10-or 52-week old were subjected to global ischemia followed by reperfusion. Mechanical function was monitored throughout the entire procedure. Activities of the respiratory chain complexes and the ratio of aconitase to fumarase activities were determined before ischemia and at the end of reperfusion. H 2 O 2 release was also evaluated in isolated mitochondria. During ischemia, middle-aged hearts displayed a delayed contracture, suggesting a maintained ATP production but also an increased metabolic proton production. Restoration of the mechanical function during reperfusion was however reduced in the middle-aged hearts, due to lower recovery of the coronary flow associated with higher mitochondrial oxidative stress indicated by the aconitase to fumarase ratio in the cardiac tissues. Surprisingly, activity of the respiratory chain complex II was better maintained in the hearts of middle-aged animals, probably because of an enhanced preservation of its membrane lipid environment. This can explain the higher mitochondrial oxidative stress observed in these conditions, since cardiac mitochondria produce much more H 2 O 2 when they oxidize FADH 2 -linked substrates than when they use NADH-linked substrates. In conclusion, the lower restoration of the cardiac mechanical activity during reperfusion in the middle-aged hearts was due to an impaired recovery of the coronary flow and an insufficient oxygen supply. The deterioration AGE (2011) of the coronary perfusion was explained by an increased mitochondrial ROS release related to the preservation of complex II activity during reperfusion.

show abstract

“…ONOO Ϫ -mediated inactivation of complex I increases O 2 ⅐ Ϫ production from that location, and O 2 ⅐ Ϫ generated by complex I is released exclusively into the matrix (16,51,(63)(64)(65). Animal I/RP models showed that, upon RP, the ETC complex activities are reduced, complex I is the main source of mitochondrial ROS (2,31,54), and NO derived from endothelial NOS (eNOS) is the one responsible for ONOO Ϫ formation, inhibition of complex I activity, and suppression of tissue O 2 consumption (84).…”

mentioning

confidence: 99%

Endothelial cell respiration is affected by the oxygen tension during shear exposure: role of mitochondrial peroxynitrite

Jones¹,

Han²,

Presley³

et al. 2008

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Cultured vascular endothelial cell (EC) exposure to steady laminar shear stress results in peroxynitrite (ONOO Ϫ ) formation intramitochondrially and inactivation of the electron transport chain. We examined whether the "hyperoxic state" of 21% O2, compared with more physiological O2 tensions (PO2), increases the shear-induced nitric oxide (NO) synthesis and mitochondrial superoxide (O2 ⅐ Ϫ ) generation leading to ONOO Ϫ formation and suppression of respiration. Electron paramagnetic resonance oximetry was used to measure O2 consumption rates of bovine aortic ECs sheared (10 dyn/cm 2 , 30 min) at 5%, 10%, or 21% O2 or left static at 5% or 21% O2. Respiration was inhibited to a greater extent when ECs were sheared at 21% O2 than at lower PO2 or left static at different PO2. Flow in the presence of an endothelial NO synthase (eNOS) inhibitor or a ONOO Ϫ scavenger abolished the inhibitory effect. EC transfection with an adenovirus that expresses manganese superoxide dismutase in mitochondria, and not a control virus, blocked the inhibitory effect. Intracellular and mitochondrial O2 ⅐ Ϫ production was higher in ECs sheared at 21% than at 5% O2, as determined by dihydroethidium and MitoSOX red fluorescence, respectively, and the latter was, at least in part, NO-dependent. Accumulation of NO metabolites in media of ECs sheared at 21% O2 was modestly increased compared with ECs sheared at lower PO2, suggesting that eNOS activity may be higher at 21% O2. Hence, the hyperoxia of in vitro EC flow studies, via increased NO and mitochondrial O2 ⅐ Ϫ production, leads to enhanced ONOO Ϫ formation intramitochondrially and suppression of respiration. shear stress; endothelium; mitochondria; reactive oxygen species MITOCHONDRIA ARE THE SUBCELLULAR organelles for the production of cellular energy, but they also activate intracellular signaling pathways that modulate cell proliferation or promote cell cycle arrest and apoptosis by oxidative or nitrosative reactions. These reactions are regulated by the matrix concentration of nitric oxide (NO), which diffuses to the mitochondria from the cytosolic NO synthase (NOS) isoforms and is thought to be produced also locally by a mitochondrial NOS variant (11). In rat heart, skeletal muscle and liver mitochondria (15,57,58), isolated rat hearts (59), and whole animals (68), NO at physiological concentrations binds reversibly and in competition with oxygen (O 2 ) to the reduced binuclear center Cu B /a 3 of cytochrome-c oxidase (complex IV) of the electron transport chain (ETC) and inhibits mitochondrial O 2 uptake. At slightly higher concentrations, NO oxidizes ubiquinol of ubiquinolcytochrome c reductase (complex III) to increase unstable ubisemiquinone, which, by univalent electron transfer to O 2 , produces the reactive O 2 species (ROS) superoxide (O 2 ⅐ Ϫ ) (57, 58). O 2 ⅐ Ϫ generated from that location is released both into the matrix and intermembrane space (51), where it is dismutated to hydrogen peroxide (H 2 O 2 ) by manganese superoxide dismutase (MnSOD) and copper zinc SOD (CuZ...

show abstract

Decrease in Mitochondrial Complex I Activity in Ischemic/Reperfused Rat Heart

Cited by 410 publications

References 56 publications

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Endothelial cell respiration is affected by the oxygen tension during shear exposure: role of mitochondrial peroxynitrite

Contact Info

Product

Resources

About