The capacity to fold and assemble nascent unfolded proteins and to degrade unassembled and misfolded proteins is important to organelle homeostasis and is regulated by unfolded protein responses activated by specific stress signals. Defects in mitochondrial protein folding play a role in important neurological diseases such as spastic paraplegia and Parkinson's disease. My goal is to understand how mitochondria regulate their ability to fold and process proteins in response to variations in unfolded protein load. I will identify genes required for signaling the mitochondrial unfolded protein response by a systematic, sequential, genome-wide survey for C. elegans genes whose inactivation by RNAi impairs the mitochondrial unfolded protein response. I will prioritize and validate the genes identified in this survey based on biochemical assays that measure mitochondrial protein folding capacity, degradation capacity and import capacity in living C. elegans. Finally I will seek to identify the mode of action of genes that signal the mitochondrial unfolded protein response. By understanding the basic principles of signaling from the mitochondria to the nucleus I expect to provide insight into pathophysiological processes involved in neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS050901-02
Application #
7116821
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Murphy, Diane
Project Start
2005-09-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$48,796
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Haynes, Cole M; Yang, Yun; Blais, Steven P et al. (2010) The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans. Mol Cell 37:529-40
Wiseman, R Luke; Chin, King-Tung; Haynes, Cole M et al. (2009) Thioredoxin-related Protein 32 is an arsenite-regulated Thiol Reductase of the proteasome 19 S particle. J Biol Chem 284:15233-45
Haynes, Cole M; Petrova, Kseniya; Benedetti, Cristina et al. (2007) ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Dev Cell 13:467-80
Benedetti, Cristina; Haynes, Cole M; Yang, Yun et al. (2006) Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response. Genetics 174:229-39