Spotlight - Cole Haynes

Working with David, I started by addressing a simple cell biology question: How do mitochondria sense the presence of unfolded proteins, and, how, then does the cell integrate this information into ongoing gene expression programs? Similar to the endoplasmic reticulum and cytoplasm, mitochondria have a dedicated molecular chaperone network, which maintains the organelle's folding capacity, facilitates protein folding, and protects against the accumulation of deleterious, aggregation-prone proteins. Much like the accumulation of unfolded protein stress in the ER, stress in mitochondria is sensed and a signal is transduced to the nucleus, where molecular chaperone genes are turned on to facilitate protein folding. However, as the cell is compartmentalized, these chaperones are targeted specifically to mitochondria. Initially, studying mitochondrial protein folding did not seem like much of a stretch from the lab's previous work, but we quickly realized the process of signaling from the mitochondria to the nucleus was much different.

Over the course of our study, we found a number of components that make up a signal transduction pathway termed the mitochondrial unfolded protein response. We ended up reporting, in Developmental Cell as well as in Molecular Cell, on a genome-wide RNAi-based screen for genes involved in signaling the mitochondrial unfolded protein response. Up to this point, the majority of the work had been done in the worm, C. elegans, a system amenable to genetic discoveries. Interestingly, all of the identified components are present in mammals, which naturally started me thinking about diseases like cancer where maintenance of mitochondrial homeostasis might play a big role.

Part of an Exciting New Team

After more than four years working in David's lab, I felt it was time to start my own lab. Given the importance of mitochondria in numerous aspects of biology and disease, I had a number of ideas for my own research, and seriously considered two institutions: The Scripps Research Institute in La Jolla, California, and Sloan-Kettering Institute (SKI). When I interviewed with Alan Hall, the chairman of the Cell Biology program here at SKI, it seemed like he was putting together an exciting and energetic group of researchers. It didn't take me long to decide that I wanted to be a part of that group and by that point I had grown accustomed to living in New York City and really enjoy all the city has to offer.

My laboratory at SKI continues to be interested in molecular mechanisms and signaling pathways that protect mitochondrial function, particularly at the level of protein folding and protein homeostasis. There is a fair amount of research into the workings of mitochondrial chaperones or proteases; however, how different biological scenarios impact the mitochondrial folding environment and the dependence on maintenance of the environment is relatively wide open. Now that we have identified the components in this signaling pathway, we intend to explore its function in aspects of biology where mitochondrial biogenesis and/or dysfunction are prevalent. Our interests range from aging, to germ line development, and to cancer.

Research Goals

One of my major goals is to further our understanding of the stress responses that cells mount to protect and maintain mitochondria and to understand how these function at the molecular level. Ultimately, we hope to develop strategies to manipulate these components as potential therapeutic strategies. For example, inhibition of such mechanisms to reduce mitochondrial folding capacity may slow cancer cell proliferation, while boosting signaling and increasing the organelle's folding capacity may allow cells to better deal with the unfolded protein stress and mitochondrial dysfunction associated with aging.

There's clearly mitochondrial dysfunction going on in cancer cells. Working at SKI, which is part of Memorial Sloan-Kettering Cancer Center, provides a fantastic environment to gain a better understanding of this dysfunction and the means by which cancer cells adapt to it. With all the alterations in mitochondria observed in a wide range of cancer cells, including increased reactive oxygen species, mutations in mitochondrial DNA as well as the shift in metabolism away from mitochondrial-dependent respiration, the organelle's protein folding environment is almost certainly stressed. This suggests a dependence on pathways that promote efficient mitochondrial protein folding. The initial work was done in worms, so there is a pretty big stretch between that and cancer patients. But we'll start with studies in cell culture and see if the components we found in worms are functioning in a similar manner in human cells and go from there.