Targeted Deletion of AIF Decreases Mitochondrial Oxidative Phosphorylation and Protects from Obesity and Diabetes

Pospisilik, J. Andrew; Knauf, Claude; Joza, Nicholas; Bénit, Paule; Orthofer, Michael; Cani, Patrice D.; Ebersberger, Ingo; Nakashima, Tomoki; Sarao, Renu; Neely, G. Gregory; Esterbauer, Harald; Kozlov, Andrey V.; Kahn, C. Ronald; Kroemer, Guido; Rustin, Pierre; Burcelin, Rémy; Penninger, Josef

doi:10.1016/j.cell.2007.08.047

Cited by 373 publications

(336 citation statements)

References 40 publications

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“…AIFM1 is attached to the inner mitochondrial membrane, where it exerts NADH oxidase activity, 48 while mutations in this gene cause oxidative phosphorylation deficiency. [49][50][51] Our biochemical apoptosis results in the translocation of AIFM1 to the nucleus, where it binds DNA and affects chromosome condensation and fragmentation, although the precise mechanism of AIFM1 nuclear function is unknown. 48,[52][53][54][55] We showed that AIFM1 knockdown in striatal cells attenuated toxicity of expanded Htt-N585-82Q fragment (Fig.…”

Section: Discussionmentioning

confidence: 99%

Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis

et al. 2012

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“…For example, we and others have shown that high-fat feeding enhances mitochondrial oxidative capacity in skeletal muscle, even though lipid accumulates and insulin resistance develops in this tissue [4,5]. Furthermore, mice with genetically induced mitochondrial dysfunction in skeletal muscle are not insulin resistant, even when challenged with a high-fat diet (HFD) [6,7]. By contrast, several studies have shown that enhancing substrate oxidation in muscle can reduce intramuscular lipid accumulation and improve insulin sensitivity [8,9].…”

Section: Introductionmentioning

confidence: 99%

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

et al. 2011

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Aims/Hypothesis To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1β [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of dietinduced insulin resistance. Methods Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1β in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1β on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp. Results Pgc-1β gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1β. In rats fed a HFD, increasing the levels of Pgc-1β partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. Conclusions Our data show that an increase in Pgc-1β expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.

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“…A decrease in the levels of mitochondrial proteins and mitochondrial DNA in adipocytes has been correlated with the development of type 2 DM [76]. In addition, insulin resistance in the elderly has been linked to fat accumulation and reduction in mitochondrial oxidative and phosphorylation activity [77,78].…”

Section: The Role Of Oxidative Stress In Dmmentioning

confidence: 99%

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

Maiese

2008

Biomedicine & Pharmacotherapy

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SummaryOxidative stress is a principal pathway for the dysfunction and ultimate destruction of cells in the neuronal and vascular systems for several disease entities, non promoting the ravages of oxidative stress to any less of a degree than diabetes mellitus. Diabetes mellitus is increasing in incidence as a result of changes in human behavior that relate to diet and daily exercise and is predicted to affect almost 400 million individuals worldwide in another two decades. Furthermore, both type 1 and type 2 diabetes mellitus can lead to significant disability in the nervous and cardiovascular systems, such as cognitive loss and cardiac insufficiency. As a result, innovative strategies that directly target oxidative stress to preserve neuronal and vascular longevity could offer viable therapeutic options to diabetic patients in addition to more conventional treatments that are designed to control serum glucose levels. Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide, Wnt signaling, and erythropoietin to outline not only the potential benefits, but also the challenges and possible detriments of these therapies. In this way, new avenues of investigation can hopefully bypass toxic complications, or at the very least, avoid contraindications that may limit care and offer both safe and robust clinical treatment for patients.

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Targeted Deletion of AIF Decreases Mitochondrial Oxidative Phosphorylation and Protects from Obesity and Diabetes

Cited by 373 publications

References 40 publications

Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis

Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

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