Mitochondria are central to energy homeostasis and numerous signaling pathways. Thus, it is no surprise that mitochondrial dysfunction has severe consequences, contributing to a wide range of aging-related pathologies, including insulin resistance, diabetes and neurodegenerative syndromes. Determining the basic cellular and molecular mechanisms that regulate mitochondrial function is pivotal in understanding and eventually treating diseases related to mitochondrial dysfunction. Expression patterns, knockout phenotypes and recently identified gene targets implicate Estrogen-Related Receptor ? (ERR?) in the regulation of mitochondrial function. As an orphan receptor with no known ligand, resolving the physiological significance of ERR? requires in-depth understanding of the signals and processes regulating its activity. The long-term goals of this project are to elucidate the pathways and mechanisms that regulate the activity of ERRp and determine how this regulation relates to mitochondrial function. Specifically, this project will seek to identify proteins and pathways involved in the activation of ERR?, as well as the basic mechanisms of this activation. To this end, the specific aims of this project are: 1) elucidation of the molecules and pathways involved in regulation of ERRP activity and 2) identification of the protein modifications contributing to this regulation. To maximize the chances of discovering significant regulators, both an unbiased cDNA genome-wide library plus a pool of potential co-regulators will be screened in an ERRP activity assay. To identify post-translational modifications that regulate ERR?, and in particular phosphorylations, mass spectrometry will be used in combination with point mutagenesis to develop a comprehensive phosphorylation map and to determine the sites that affect ERR? activity. Determining the molecular mechanisms by which ERR? is regulated will provide insight into the specific physiological role of this orphan nuclear receptor as it relates to mitochondrial function and dysfunction. Relevance: Aging-related pathologies, including insulin resistance, diabetes and neuromuscular degenerative syndromes affect a huge proportion of the population and therefore significantly impact public health. Defects in mitochondrial function are thought to contribute to these pathologies. Understanding the basic biological mechanisms regulating mitochondrial function is essential for understanding how dysfunction arises, how this translates to disease, and how dysfunction can be treated and ultimately prevented.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG033487-04
Application #
8312538
Study Section
Special Emphasis Panel (ZRG1-F06-E (20))
Program Officer
Fuldner, Rebecca A
Project Start
2009-08-15
Project End
2013-08-14
Budget Start
2012-08-15
Budget End
2013-08-14
Support Year
4
Fiscal Year
2012
Total Cost
$32,652
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Gantner, Marin L; Hazen, Bethany C; Conkright, Juliana et al. (2014) GADD45? regulates the thermogenic capacity of brown adipose tissue. Proc Natl Acad Sci U S A 111:11870-5