Control of mitochondrial superoxide production by reverse electron transport at complex I

Robb, Ellen L.; Hall, Andrew; Prime, Tracy A.; Eaton, Simon; Szibor, Marten; Viscomi, Carlo; James, Andrew M.; Murphy, Michael P.

doi:10.1074/jbc.ra118.003647

Cited by 243 publications

(250 citation statements)

References 51 publications

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“…In addition to compromise the mitochondrial respiratory chain activity, inhibition of CxIII is well-known to enhance ROS production 35 . This appears to be due to accumulation of reactive radical intermediates, which are intrinsic to the catalytic cycle of the CxIII, and in addition to a phenomenon defined as "reverse electron transfer" that move reducing equivalents from ubiquinol back through the CxI, which becomes under this condition a further ROS generator 28,36 . Accordingly, we detected enhanced production of ROS, following nandrolone-treatment, traceable back to the mitochondrial compartment.…”

Section: Discussionmentioning

confidence: 99%

Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial respiratory activity

Agriesti

Tataranni

Pacelli

et al. 2020

Sci Rep

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nandrolone is a testosterone analogue with anabolic properties commonly abused worldwide, recently utilized also as therapeutic agent in chronic diseases, cancer included. Here we investigated the impact of nandrolone on the metabolic phenotype in HepG2 cell line. The results attained show that pharmacological dosage of nandrolone, slowing cell growth, repressed mitochondrial respiration, inhibited the respiratory chain complexes i and iii and enhanced mitochondrial reactive oxygen species (ROS) production. Intriguingly, nandrolone caused a significant increase of stemness-markers in both 2D and 3D cultures, which resulted to be CxIII-ROS dependent. Notably, nandrolone negatively affected differentiation both in healthy hematopoietic and mesenchymal stem cells. Finally, nandrolone administration in mice confirmed the up-regulation of stemness-markers in liver, spleen and kidney. Our observations show, for the first time, that chronic administration of nandrolone, favoring maintenance of stem cells in different tissues would represent a precondition that, in addition to multiple hits, might enhance risk of carcinogenesis raising warnings about its abuse and therapeutic utilization.

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Section: Discussionmentioning

confidence: 99%

Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial respiratory activity

Agriesti

Tataranni

Pacelli

et al. 2020

Sci Rep

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“…AOX was previously demonstrated to blunt RET-induced ROS production under various conditions. 33,34,36,37 We therefore first tested whether the extent of acute I/R injury (infarct size) would be decreased in the post-ischaemic heart of mice with excellent cardiac AOX protein expression and catalytic AOX activity. 33 Using the open-chest in situ I/R model, 41 30 minutes of ischaemia were applied by occluding the left anterior descending (LAD) coronary artery followed by 2 hours of reperfusion in wild-type (WT) and AOX littermates.…”

Section: Aox Does Not Decrease Acute I/r Injuriesmentioning

confidence: 99%

Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

Szibor

Schreckenberg

Gizatullina

et al. 2020

J Cellular Molecular Medi

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Cardiac ischaemia‐reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS production. Hence, AOX represents a natural rescue mechanism from respiratory stress. This study aimed to determine how respiratory restoration through xenotopically expressed AOX affects the re‐perfused post‐ischaemic mouse heart. As expected, AOX supports ETC function and attenuates the ROS load in post‐anoxic heart mitochondria. However, post‐ischaemic cardiac remodelling over 3 and 9 weeks was not improved. AOX blunted transcript levels of factors known to be up‐regulated upon I/R such as the atrial natriuretic peptide (Anp) whilst expression of pro‐fibrotic and pro‐apoptotic transcripts were increased. Ex vivo analysis revealed contractile failure at nine but not 3 weeks after ischaemia whilst label‐free quantitative proteomics identified an increase in proteins promoting adverse extracellular matrix remodelling. Together, this indicates an essential role for ETC‐derived signals during cardiac adaptive remodelling and identified ROS as a possible effector.

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“…In addition to the extramitochondrial source of superoxide anion, its mitochondrial generation is a collateral consequence of respiration in the MRC . (Fig.…”

Section: Oxidative Stress: Concept Sources and Defensesmentioning

confidence: 99%

Mitochondrial Oxidative Stress and Antioxidants Balance in Fatty Liver Disease

2018

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Fatty liver disease is one of the most prevalent forms of chronic liver disease that encompasses both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are intermediate stages of ALD and NAFLD, which can progress to more advanced forms, including cirrhosis and hepatocellular carcinoma. Oxidative stress and particularly alterations in mitochondrial function are thought to play a significant role in both ASH and NASH and recognized to contribute to the generation of reactive oxygen species (ROS), as documented in experimental models. Despite the evidence of ROS generation, the therapeutic efficacy of treatment with antioxidants in patients with fatty liver disease has yielded poor results. Although oxidative stress is considered to be the disequilibrium between ROS and antioxidants, there is evidence that a subtle balance among antioxidants, particularly in mitochondria, is necessary to avoid the generation of ROS and hence oxidative stress. Conclusion: As mitochondria are a major source of ROS, the present review summarizes the role of mitochondrial oxidative stress in ASH and NASH and presents emerging data indicating the need to preserve mitochondrial antioxidant balance as a potential approach for the treatment of human fatty liver disease, which may pave the way for the design of future trials to test the therapeutic role of antioxidants in fatty liver disease.

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Control of mitochondrial superoxide production by reverse electron transport at complex I

Cited by 243 publications

References 51 publications

Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial respiratory activity

Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial respiratory activity

Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

Mitochondrial Oxidative Stress and Antioxidants Balance in Fatty Liver Disease

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