Cole Haynes: On the trail of mitochondrial dysfunction

Since graduate school at the University of Missouri, Cole Haynes has been preoccupied with how mixed up, misfolded proteins inside organelles affect the well-being of cells. At Missouri, he studied the classic pathway: how rumpled proteins are recognized in the yeast endoplasmic reticulum and ultimately targeted for degradation. As a postdoctoral fellow, he went a little more cosmopolitan, moving to David Ron's lab at New York University School of Medicine to investigate how cells adapt to the stress of unfolded proteins in mitochondria. Working in C. elegans, the team began cracking the signaling involved in the mito-chondrial unfolded protein response (UPR mt) (1), a line of inquiry that Haynes brought with him to his own laboratory at Memorial Sloan Kettering Cancer Center in 2009. He identifi ed both the matrix peptide exporter HAF-1 (2) and the import effi ciency of the transcription factor ATFS-1 (3) as key signals for activating the UPR mt. In 2012, his laboratory discovered that the kinase GCN-2 acts to slow protein synthesis in response to mitochondrial stress (4)—a pathway that complements the ATFS-1 pathway, which, among other things, sends more mitochondrial chaperones to the scene (3). Currently, the Haynes lab explores the roles mitochon-drial stress responses might play in aging, cancer, and innate immunity (5). He recently spoke with JCB about his longtime love of unfolded proteins and organelle maintenance. Why do misfolded proteins fascinate you? Maintaining the status of the proteome is clearly a basic and important problem. Protein folding defects are at the heart of all sorts of mammalian pathologies. There are tons of examples of protein misfolding causing problems. It's an aging problem. It's a disease problem. The topic touches on various aspects of physiology that I think are cool. Why use worms to study the UPR mt ? Worms have about 20,000 genes and they are metazoan, so their mitochondrial functions probably resemble ours more closely than yeast's do. But the biggest advantage of the worm early on was that the RNAi library was available. That made it relatively easy to identify components of this mito-chondrial-to-nuclear signaling pathway. You can also use RNAi to knock down just about any respiratory chain or mito-chondrial chaperone gene to induce mito-chondrial stress in worms. Almost any sort of global hit to mitochondrial activity will induce the UPR mt. How did you discover that ATFS-1 is an important regulator of the UPR mt ? David …