Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase.

Pitkänen, Sari; Robinson, Brian H.

doi:10.1172/jci118798

Cited by 364 publications

(226 citation statements)

References 23 publications

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“…There are several reasons to hypothesize that mitochondrial abnormalities might be associated with increased oxidative stress: (1) the ultrastructural changes of the mitochondria in peroxisome-deficient hepatocytes are similar to the alterations observed in conditions of oxidative stress 39 ; (2) defects in complex I, the main production site of reactive oxygen species in mitochondria, 40 lead to an increased radical production 41,42 ; and (3) the activity of complex I can be severely impaired as a result of oxidative stress. 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.…”

Section: Discussionmentioning

confidence: 99%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

et al. 2005

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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...

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Section: Discussionmentioning

confidence: 99%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

et al. 2005

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“…Complex I defects increase cellular production of ROS, which may influence Mn SOD expression (93). Reoxygenated kidney tubule cells develop energy deficits due to complex I dysfunction that occur before onset of the mitochondrial permeability transition (MPT) or loss of cytochrome c. Supplementation with citric acid cycle metabolites that anaerobically generate ATP may prevent energy deficits (125).…”

Section: Effects Of Reoxygenation On Mitochondrial Functionmentioning

confidence: 99%

Reactive species mechanisms of cellular hypoxia-reoxygenation injury

Jackson

2002

American Journal of Physiology-Cell Physiology

937

673

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Li, Chuanyu, and Robert M. Jackson. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol 282: C227-C241, 2002; 10.1152/ajpcell.00112.2001.-Exacerbation of hypoxic injury after restoration of oxygenation (reoxygenation) is an important mechanism of cellular injury in transplantation and in myocardial, hepatic, intestinal, cerebral, renal, and other ischemic syndromes. Cellular hypoxia and reoxygenation are two essential elements of ischemia-reperfusion injury. Activated neutrophils contribute to vascular reperfusion injury, yet posthypoxic cellular injury occurs in the absence of inflammatory cells through mechanisms involving reactive oxygen (ROS) or nitrogen species (RNS). Xanthine oxidase (XO) produces ROS in some reoxygenated cells, but other intracellular sources of ROS are abundant, and XO is not required for reoxygenation injury. Hypoxic or reoxygenated mitochondria may produce excess superoxide (O 2 Ϫ ) and release H2O2, a diffusible long-lived oxidant that can activate signaling pathways or react vicinally with proteins and lipid membranes. This review focuses on the specific roles of ROS and RNS in the cellular response to hypoxia and subsequent cytolytic injury during reoxygenation.anoxia; ischemia; reperfusion BACKGROUND

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“…Studies analyzing the impact of mutations in mtDNA-encoded genes on ROS production in different mitochondrial disease models (fibroblasts, transmitochondrial cybrids and neuronal NT2 cells) have frequently revealed increased ROS levels (Pitkanen and Robinson, 1996;Rana et al, 2000;Geromel et al, 2001;Wong et al, 2002;Beretta et al, 2004;Floreani et al, 2005;Gonzalo et al, 2005;Vives-Bauza et al, 2006). The deleterious effect of each mutation could be influenced by the genetic background of a specific patient, as the biosynthesis of the OXPHOS complexes implies the interaction between many different subunits and regulatory factors.…”

Section: Role Of the Mtdna Genetic Background On The Rc Dysfunction Amentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

140

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase.

Cited by 364 publications

References 23 publications

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

Reactive species mechanisms of cellular hypoxia-reoxygenation injury

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

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