A mitochondrial longevity pathway: p66Shc mechanisms The long-term objective of this application is to understand how deficiency of the p66Shc protein extends lifespan by >30% in mice, using an interdisciplinary approach that integrates levels of biological organization progressing from biochemical, molecular, organellar, cellular, bioenergetic, pathological, and to the whole organism level. As background, genetic deficiencies in the IGF-lnsR axis have been demonstrated to extend lifespan in flies, worms, and mice;5 of 6 known lifespan-extension mutations in mice are in the IGF-lnsR pathway. The sixth mutation, in p66Shc, causes a modest decrease in size that is focused on adipose tissue, and thus less severe than in other models;preliminary data show transcripts of the IGF-lnsR axis modified in p66Shc-deficient tissues. P66Shc has a redox activity that is essential for its biological functions, including generation of reactive oxygen species (ROS), apoptosis, adipogenesis, and angiogenesis. P66Shc functions in both mitochondrial and cytoplasmic compartments, and it interacts directly with components of the mitochondrial respiratory chain. Therefore, we will elucidate the physiological functions of p66Shc and the mechanism by which deficiencies of these functions extend lifespan, by an interdisciplinary and integrative study. In Project 1, the biochemical structure, function, and partners of p66Shc will be clarified, as well as the consequences of p66Shc for metabolic syndrome (e.g., a mechanism by which adiposity leads to disease). In Project 2, the stimuli for p66Shc recruitment to the mitochondria and plasma membrane will be studied, as well as the mitochondrial consequences of p66Shc recruitment. In Project 3, microarray and proteomics will be performed, to assess the primary consequences of p66Shc deficiency in relevant cell types. And, in Project 4, the metabolic and bioenergetic underpinnings of lifespan extension by p66Shc-deficiency will be determined. Core A will support weekly meetings and continuous data flow to catalyze synergistic interactions;Core B will provide backcrossed and barrier-derived animals and expertise in mouse pathology to determine the category(ies) of morbidity retarded by p66Shc deficiency;and Core C will provide support for optimum study design and robust biostatistical analysis.

Public Health Relevance

to public health: The conserved nature of the IGF-lnsR axis pathway for lifespan extension worms and mice, and the impact of p66Shc on adiposity, suggests that elucidation of the p66Shc will likely be relevant to human health in the United States.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG025532-04
Application #
7798966
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (O3))
Program Officer
Finkelstein, David B
Project Start
2007-06-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$1,434,113
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
McMackin, Marissa Z; Henderson, Chelsea K; Cortopassi, Gino A (2017) Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia. Behav Brain Res 316:183-188
Granatiero, Veronica; Gherardi, Gaia; Vianello, Matteo et al. (2017) Role of p66shc in skeletal muscle function. Sci Rep 7:6283
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
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
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
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
Taylor, Sandra L; Ruhaak, L Renee; Kelly, Karen et al. (2017) Effects of imputation on correlation: implications for analysis of mass spectrometry data from multiple biological matrices. Brief Bioinform 18:312-320
Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise et al. (2017) The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Invest Ophthalmol Vis Sci 58:2406-2412
Hagopian, Kevork; Kim, Kyoungmi; López-Dominguez, José Alberto et al. (2016) Mice with low levels of Shc proteins display reduced glycolytic and increased gluconeogenic activities in liver. Biochem Biophys Rep 7:273-286
Datta, Sandipan; Tomilov, Alexey; Cortopassi, Gino (2016) Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations. Mitochondrion 30:177-86

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