My research focuses on mitochondria, membrane-bound compartments found in eukaryotic cells. In addition to their well-known role in ATP biosynthesis, mitochondria have a wide variety of other functions, including regulating programmed cell death pathways, controlling calcium and iron homeostasis, coordinating reactive oxygen species production, and providing essential intermediates for cholesterol biosynthesis. Given this broad purview, it is not surprising that mitochondrial dysfunction is increasingly recognized as a key contributor to a wide variety of diseases and aging. We research mitochondrial homeostasis and surveillance and the relationships of these processes to health and disease.
1) How do bacteria affect mitochondria? We use the model nematode C. elegans and human cell lines to characterize host-pathogen interactions and their impact on mitochondria. Most of our research focuses on the Gram-negative pathogen Pseudomonas aeruginosa, but we also work with Enterococcus faecalis and E. faecium, Staphylococcus aureus, and Candida albicans.
2) How do mitochondrial surveillance networks function? We study the evolutionarily conserved ESRE (Ethanol and Stress Response Element) mitochondrial network, which is activated by increased levels of reactive oxygen species. We are characterizing how the ESRE pathway is regulated and how it interacts with other mitochondrial surveillance pathways and how this impacts host homeostasis.
3) Can modulating mitochondrial homeostasis improve neuronal function? We identified several FDA-approved antidepressants that delay the onset of symptoms of neurodegenerative disease in C. elegans models. We are characterizing the mechanisms of action for these molecules as they are distinct from their canonical role. In addition, using high-throughput drug screening, we identified novel small molecules that decrease protein aggregation. Mechanistic characterizations are ongoing.
4) Can mitochondrial metabolism be harnessed to kill cancer cells? Acute myeloid leukemia (AML) is a type of hematological cancer that heavily relies on oxidative phosphorylation. We identified novel small molecules that inhibit glutathione reductase, increasing reactive oxygen species, rapid mitochondrial recycling, and rapid AML death. Our subsequent research characterizes the therapeutic potential of these molecules.
In addition, we are working on identifying novel ways to target multidrug-resistant P. aeruginosa. These involve inhibition of virulence factors or killing bacteria using pyocins – needle-like protein complexes that are highly specific to Pseudomonas and can kill bacteria regardless of their drug-resistance traits.