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.
| 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 |
