Project 2: Translocations of p66Shc: kinetics, function, apoptosisThe overall goal of this project is to understand the mechanism that drives the organellar translocation ofp66Shc, how p66Shc influences mitochondrial parameters once it arrives there, and how these triggerapoptosis and then to design inhibitors of this translocation process as de facto p66Shc inhibitors/Thus,Specific Aims for this project are to:(1) Identify the link between reactive oxygen species exposure and She recruitment; we will identify (i) theupstream kinases leading to the phosphorylation of Ser36 and (ii) the cellular systems that recognize andactivate the phosphorylated protein. We expect that peptidyl-prolyl-isomerase recognizes thephosphorylation of p66Shc and therefore is critical for the apoptotic effect.(2) Measure stress-dependent translocation of p66shc to mitochondria. We will identify the mechanism,timing, and regulation of the translocation of p66shcto the mitochondrial inter-membrane space; we willevaluate the localization of p66Shc to the ER-mitochondrial contact sites and the interaction of p66Shc withother molecules we have previously demonstrated to be involved in ER-to-mitochondrial signaling.(3) Investigate the consequences of p66Shc activation on mitochondria. We will clarify the consequences ofp66shc activation on mitochondria, including (i) mitochondrial calcium homeostasis, (ii) mitochondrialmembrane potential, (iii) 3D mitochondrial structure, and (iv)ATP production.(4) Examine the mechanism of apoptosis following p66Shc activation. We will test the participation of twobasic mitochondrial mechanisms of apoptosis induction, measure mitochondrial depolarization as a hallmarkof mitochondrial permeability transition (MPT), and then evaluate the interaction of p66Shc pathways withBcl-2 pathways by coexpressing isoforms of each.(5) Develop novel tools to identify drugs acting on the She signaling pathway; we will develop two cell-basedassays, suitable for use in high-throughput screenings, to address the potential for She-like therapeutics.Relevance to public health: Because the p66Shc pathway appears to be related to the IGF-lnsR pathway oflifespan extension that extends lifespan from flies to mice, and because p66Shc appears to controladipogenesis and may be related to metabolic syndrome, it is likely that our experiments and search forp66Shc recruitment inhibitors will be relevant to public health.
| Roberts, Megan N; Wallace, Marita A; Tomilov, Alexey A et al. (2018) A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab 27:1156 |
| Penna, Elisa; Espino, Javier; De Stefani, Diego et al. (2018) The MCU complex in cell death. Cell Calcium 69:73-80 |
| Pallafacchina, Giorgia; Zanin, Sofia; Rizzuto, Rosario (2018) Recent advances in the molecular mechanism of mitochondrial calcium uptake. F1000Res 7: |
| Jasoliya, Mittal J; McMackin, Marissa Z; Henderson, Chelsea K et al. (2017) Frataxin deficiency impairs mitochondrial biogenesis in cells, mice and humans. Hum Mol Genet 26:2627-2633 |
| Song, Lanying; Yu, Alfred; Murray, Karl et al. (2017) Bipolar cell reduction precedes retinal ganglion neuron loss in a complex 1 knockout mouse model. Brain Res 1657:232-244 |
| Roberts, Megan N; Wallace, Marita A; Tomilov, Alexey A et al. (2017) A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab 26:539-546.e5 |
| Taylor, Sandra L; Ruhaak, L Renee; Weiss, Robert H et al. (2017) Multivariate two-part statistics for analysis of correlated mass spectrometry data from multiple biological specimens. Bioinformatics 33:17-25 |
| Hayashi, Genki; Jasoliya, Mittal; Sahdeo, Sunil et al. (2017) Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Hum Mol Genet 26:2864-2873 |
| Wright, Lauren E; Vecellio Reane, Denis; Milan, Gabriella et al. (2017) Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance. Am J Physiol Endocrinol Metab 313:E641-E650 |
| Baldassini, W A; Ramsey, J J; Hagopian, K et al. (2017) The influence of Shc proteins and high-fat diet on energy metabolism of mice. Cell Biochem Funct 35:527-537 |
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