Khalid 2016 Abstract Mito Xmas Meeting Innsbruck

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Prevention of mitochondrial oxidative damage: Novel insights into the activation of the pro-oxidant and pro-death function of p66Shc.

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Khalid S, Haller M, Kremser L, Fresser F, Furlan T, Hermann M, Guenther J, Drasche A, Leitges M, Giorgio M, Baier G, Lindner H, Troppmair J (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

Excessive production of reactive oxygen species (ROS) has been causally linked to cell death resulting in loss of cognitive or organ function. Diseases range from neurodegeneration, stroke, diabetes, to ischemia/reperfusion injury (IRI). Antioxidants failed in the clinical setting. Also the direct inhibition of mitochondrial and non-mitochondrial ROS producing systems is not clinically feasible. Among those sources p66Shc is unique as its knockout did not affect normal development while it prevented or ameliorated ROS-induced pathophysiological changes. p66Shc normally resides in the cytoplasm. Previous work suggested that activation of the pro-oxidant and pro-death function of p66Shc required phosphorylation on serine 36 (S36) followed by mitochondrial import and PKCβ has been proposed as S36 kinase. Due to the lack of inhibitors of its oxidoreductase function we pursue a strategy to inhibit p66Shc by interfering with its upstream activation. To this end we initiated a detailed analysis of the mechanisms controlling p66Shc activity and function. We confirmed the requirement of PKCβ for ROS production and cell death but not for p66ShcS36 phosphorylation. The search for a bona Prevention of oxidative damage fide S36 kinase lead to JNK1/2, whose involvement was confirmed through the use of inhibitors and JNK1/2-deficient cells. Moreover, expression of a S36E mutant in p66Shc-deficient rescued ROS production. Additionally, we identified S139, T206 and S213 as the critical PKCβ target sites regulating the pro-oxidant and pro-death function of p66Shc. JNK1/2 and PKCß are normally activated under cellular stress and targeting them offers a novel therapeutic approach to prevent diseases associated with excessive ROS production.


Labels: MiParea: mt-Medicine  Pathology: Cardiovascular, Other  Stress:Cell death, Ischemia-reperfusion, Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Heart, Fibroblast  Preparation: Intact cells 



Event: B1, Oral  Labelled by author 

Affiliations

Khalid S(1), Haller M(1), Kremser L(2), Fresser F(3), Furlan T(1), Hermann M(4), Guenther J(1), Drasche A(1), Leitges M(5), Giorgio M(6), Baier G(3), Lindner H(2), Troppmair J(1)
  1. D. Swarovski Research Lab, Dept Visceral, Transplant Thoracic Surgery, Innsbruck Medical Univ, Austria
  2. Div Clinical Biochem, Protein Micro-Analysis Facility, Innsbruck Medical Univ, Austria
  3. Dept Pharmacology Genetics, Div Translational Cell Genetics, Innsbruck Medical Uni, Austria
  4. Dept Anesthesiology Intensive Care, Innsbruck Medical Univ, Austria
  5. Biotechnology Center Oslo, Norway
  6. European Inst Oncology, Milano, Italy