Collaborative work between the Biology and Chemistry Departments at Boston College recently resulted in the cover article of the prestigious Chemistry and Biology journal, August 27, 2007 issue.  The work was conducted by scientists at Boston College in Dr. Thomas Chiles and Dr. Shana Kelley laboratories.  Dr. Kelley (now at the University of Toronto) and members of her lab designed and characterized subcellular probes of oxidative stress in the Chemistry Department at Boston College.  Dr. Chiles (Department Chair, Department of Biology) and his lab worked to elucidate the biological response to these compounds.  Authors of the paper include several researchers at Boston College, including Kerry Mahon (Ph.D. 2006, Department of Chemistry), Terra Potocky (Postdoctoral Scientist, Departments of Chemistry and Biology), Derek Blair (Postdoctoral Scientist, Department of Biology), and Marc Roy (Ph.D. 2006, Dept. of Chemistry).

“Oxidative stress” can be described as the imbalance between reactive oxygen species (ROS) production and the antioxidant capacity of the cell. Oxidative stress has been implicated in many human diseases including cancer, atherosclerosis, Parkinson’s disease, and Alzheimer’s disease.  However, further investigations are necessary to understand the role of oxidative stress in these diseases. 

The location of ROS within a cell is one of the most important factors when studying oxidative stress and the cellular response to it. So far, most studies have been conducted using oxidants that diffuse freely throughout the cell. Thus, existing models did not account for possible differences between stress originating within particular regions of the cell.  The collaboration between Professors Kelley's and Chiles's research labs resulted in significant advances in the deconvolution of the cellular oxidative stress responses at the subcellular level. 

The Kelley Lab designed two peptidoconjugates that localized to two different organelles within the cellular environment, specifically the nucleus and mitochondria.  These compounds were then irradiated to induce reactive oxygen species production site specifically within the cells.  The ability of these compounds to induce a cytotoxic response was evaluated, resulting in the finding that nuclear localized stress induces a higher cytotoxic response than mitochondrial localized stress.  Confocal fluorescence microscopy was employed to determine subcellular localization of the probes, as well as to visualize morphological changes brought on by oxidative stress.

In conjunction with the Chiles Lab, the mechanism of cell death was probed using flow cytometry.  Mitochondrial and nuclear oxidative stress also induced different signaling pathways in these cells, indicating that cells will respond differently depending on the origin of stress. 

Conclusions:

As a result of a productive collaboration between the Biology and Chemistry Departments at BC, the authors have developed a new approach to examine oxidative stress induction in situ on the subcellular level. In addition to providing important information about the oxidative stress response, the finding that nuclear and mitochondrial oxidative stress exert dif­ferent levels of cell death and a different cellular re­sponse has important implications for the develop­ment of improved agents for photodynamic therapy (PDT), a method used to treat certain types of cancer. Kelley and Chiles et al. have also demonstrated that the oxidative stress response can be studied and sep­arated into discrete components, and that stress originating in different organelles is linked to unique biological responses.