Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates

Larosche, Isabelle; Choumar, Amal; Fromenty, Bernard; Lettéron, Philippe; Abbey-Toby, Adjé; Remmen, Holly Van; Epstein, Charles J.; Richardson, Arlan; Feldmann, Gérard; Pessayre, Dominique; Mansouri, Abdellah

doi:10.1016/j.taap.2008.11.004

Cited by 34 publications

(50 citation statements)

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“…However, antioxidant therapy studies have yielded results that range from disappointing to a potentially detrimental effect of antioxidants (24,69,81,116). Other approaches that raise or lower mitochondrial antioxidant capacity have also yielded conflicting results (63,121). These findings point to a more complex interaction of ROS within the mitochondria and suggest that alternative pathways may mediate the effect of ROS on mitochondria and mtDNA integrity.…”

Section: Discussionmentioning

confidence: 99%

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hicks

Labinskyy

Piteo

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat. Am J Physiol Heart Circ Physiol 304: H903-H915, 2013. First published February 1, 2013 doi:10.1152/ajpheart.00567.2012.-Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic GotoKakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H 2O2 suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetesinduced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium. diabetic cardiomyopathy; type 2 diabetes; mitochondrial DNA damage; mitochondrial dysfunction CARDIOVASCULAR DISEASE is responsible for a higher incidence of mortality in diabetics than the general population. Diabetic cardiomyopathy (DCM) is characterized by the development of a myopathy that manifests initially as diastolic dysfunction, but evolves into increased cavitary dilation and mural thinning, which is reflective of decompensated eccentric hypertrophy. DCM is considered to be independent of atherosclerosis or hypertension but is exacerbated by either (94). Mitochondrial dysfunction has long been known to have a significant role in the development and complications of DCM (32,46,66,82,92). Mitochondrial dysfunction is also associated with other pathologies including cancer, skeletal muscle disorders, and neurodegenerative diseases such as Wolfram syndrome or Leber's hereditary optic neuropathy (LHON) (18,36,54,104).Separate from inborn errors, mitochondrial DNA (mtDNA) mutations are thought to accumul...

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Section: Discussionmentioning

confidence: 99%

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hicks

Labinskyy

Piteo

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Migration was performed at 4°C for 12 h at 120 V, and superoxide dismutase activity was assessed within the gel, as described previously (Sutton et al, 2005). Liver mitochondria were prepared as described previously (Larosche et al, 2009). GPx activity was measured in mitochondrial fractions by following the conversion of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) into oxidized nicotinamide-adenine dinucleotide phosphate (NADP ϩ ) at 340 nm for 2 min in the presence of hydrogen peroxide, glutathione reductase, and reduced glutathione (Larosche et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…GPx activity was measured in mitochondrial fractions by following the conversion of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) into oxidized nicotinamide-adenine dinucleotide phosphate (NADP ϩ ) at 340 nm for 2 min in the presence of hydrogen peroxide, glutathione reductase, and reduced glutathione (Larosche et al, 2009). The mitochondrial content of reduced glutathione was determined by the method of Tietze (Larosche et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…The iron chelator deferoxamine prevented both iron accumulation and mtDNA depletion, suggesting that iron-mediated hydroxyl radical formation played a role in the mtDNA damage caused by prolonged alcohol administration in MnSOD ϩϩϩ mice (Larosche et al, 2009). Unlike prolonged alcohol administration, a single alcohol binge may not increase hepatic iron stores.…”

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confidence: 95%

“…We have shown that MnSOD-overexpressing (MnSOD ϩϩϩ ) transgenic mice, but not wild-type (WT) mice, developed increased hepatic iron concentrations and mtDNA depletion after 7 weeks of alcohol treatment (Larosche et al, 2009). The iron chelator deferoxamine prevented both iron accumulation and mtDNA depletion, suggesting that iron-mediated hydroxyl radical formation played a role in the mtDNA damage caused by prolonged alcohol administration in MnSOD ϩϩϩ mice (Larosche et al, 2009).…”

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Hepatic Mitochondrial DNA Depletion after an Alcohol Binge in Mice: Probable Role of Peroxynitrite and Modulation by Manganese Superoxide Dismutase

Larosche¹,

Lettéron²,

Berson³

et al. 2009

J Pharmacol Exp Ther

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Alcohol consumption increases reactive oxygen species (ROS) formation, which can damage mitochondrial DNA (mtDNA) and alter mitochondrial function. To test whether manganese superoxide dismutase (MnSOD) modulates acute alcohol-induced mitochondrial alterations, transgenic MnSOD-overexpressing (MnSOD ϩϩϩ ) mice, heterozygous knockout (MnSOD ϩ/Ϫ ) mice, and wild-type (WT) littermates were sacrificed 2 or 24 h after intragastric ethanol administration (5 g/kg). Alcohol administration further increased MnSOD activity in MnSOD ϩϩϩ mice, but further decreased it in MnSOD ϩ/Ϫ mice. In WT mice, alcohol administration transiently increased mitochondrial ROS formation, decreased mitochondrial glutathione, depleted and damaged mtDNA, and decreased complex I and V activities; alcohol durably increased inducible nitric-oxide synthase (NOS) expression, plasma nitrites/nitrates, and the nitration of tyrosine residues in complex V proteins. These effects were prevented in MnSOD ϩϩϩ mice and prolonged in MnSOD ϩ/Ϫ mice. In alcoholized WT or MnSOD ϩ/Ϫ mice, mtDNA depletion and the nitration of tyrosine residues in complex I and V proteins were prevented or attenuated by cotreatment with tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), a superoxide scavenger; N

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Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases

Mooli

Mukhi

Ramakrishnan

2022

Comprehensive Physiology

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Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates

Cited by 34 publications

References 46 publications

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hepatic Mitochondrial DNA Depletion after an Alcohol Binge in Mice: Probable Role of Peroxynitrite and Modulation by Manganese Superoxide Dismutase

Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases

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