Publications (251) View all
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Article: Convergent mechanisms for dysregulation of mitochondrial quality control in metabolic disease: implications for mitochondrial therapeutics.
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ABSTRACT: Mitochondrial dysfunction is associated with a broad range of pathologies including diabetes, ethanol toxicity, metabolic syndrome and cardiac failure. It is now becoming clear that maintaining mitochondrial quality through a balance between biogenesis, reserve capacity and mitophagy is critical in determining the response to metabolic or xenobiotic stress. In diseases associated with metabolic stress, such as Type II diabetes and non-alcoholic and alcoholic steatosis, the mitochondria are subjected to multiple 'hits' such as hypoxia and oxidative and nitrative stress, which can overwhelm the mitochondrial quality control pathways. In addition, the underlying mitochondrial genetics that evolved to accommodate high-energy demand, low-calorie supply environments may now be maladapted to modern lifestyles (low-energy demand, high-calorie environments). The pro-oxidant and pro-inflammatory environment of a sedentary western lifestyle has been associated with modified redox cell signalling pathways such as steatosis, hypoxic signalling, inflammation and fibrosis. These data suggest that loss of mitochondrial quality control is intimately associated with the aberrant activation of redox cell signalling pathways under pathological conditions. In the present short review, we discuss evidence from alcoholic liver disease supporting this concept, the insights obtained from experimental models and the application of bioenergetic-based therapeutics in the context of maintaining mitochondrial quality.Biochemical Society Transactions 02/2013; 41(1):127-33. · 3.71 Impact Factor -
Article: Mitochondrially targeted compounds and their impact on cellular bioenergetics.
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ABSTRACT: Mitochondria are recognized as critical sites of localized injury in a number of chronic pathologies which has led to the development of organelle directed therapeutics. One of the approaches employed to target molecules to the mitochondrion is to conjugate a delocalized cation such as triphenylphosphonium (TPP(+)) to various redox active compounds. Mitochondrially targeted antioxidants have also been used in numerous cell culture based studies as probes of the contribution of the mitochondrial generation of reactive oxygen species on cell signaling events. However, concentrations used in vitro are typically 10-100 times greater than those generated from oral dosing in a wide range of animal models and in humans. In the present study, we determined the effects of mitochondrial targeted antioxidants, MitoQ, MitoTempol, and MitoE on cellular bioenergetics of mesangial cells in culture and compared these to TPP(+) conjugated compounds which lack the antioxidant functional group. We found that all TPP(+) compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional groups. These findings show that the TPP(+) moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture and this behavior is dependent on the linker group and independent of antioxidant properties. Moreover, TPP(+) moiety alone is unlikely to achieve the concentrations needed to contribute to the protective mechanisms of the mitochondrially targeted compounds that have been reported in vivo.Redox biology. 01/2013; 1(1):86-93. -
Article: Controlling Radicals in the Powerhouse: Development of MitoSOD.
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ABSTRACT: Investigators in the redox biology field have long recognized the unique role mitochondrial superoxide generation plays in physiological signaling and in dysregulated bioenergetic dysfunction. Pharmacological manipulation has been challenging, and in this issue of Chemistry & Biology, Kelso and colleagues present the synthesis and characterization of a novel mitochondrial-targeted SOD mimetic, MitoSOD.Chemistry & biology 10/2012; 19(10):1217-8. · 6.52 Impact Factor -
Article: Metabolic syndrome and mitochondrial dysfunction: insights from preclinical studies with a mitochondrially targeted antioxidant.
Free radical biology & medicine 03/2012; 52(5):838-40. · 5.42 Impact Factor -
Article: Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations.
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ABSTRACT: The purpose of this position paper is to present a critical analysis of the challenges and limitations of the most widely used fluorescent probes for detecting and measuring reactive oxygen and nitrogen species. Where feasible, we have made recommendations for the use of alternate probes and appropriate analytical techniques that measure the specific products formed from the reactions between fluorescent probes and reactive oxygen and nitrogen species. We have proposed guidelines that will help present and future researchers with regard to the optimal use of selected fluorescent probes and interpretation of results.Free radical biology & medicine 01/2012; 52(1):1-6. · 5.42 Impact Factor
