Mitochondria in cancer metabolism
Resistance to cell death and reprogramming of energy metabolism are two prominent features of cancer cells. Mitochondria are known to be intimately linked to both these features and are believed to play a key role in a diversity of processes contributing to the metabolic plasticity and growth of cancer cells. While some cancer types seem to have undergone a metabolic shift to utilize glycolysis for generation of ATP, a number of malignant tumor cells rely mainly on oxidative phosphorylation (OXPHOS) to support their proliferation. Mitochondrial substrates are also utilized in tumour cells for anabolic growth. The process of ATP production through OXPHOS and substrates production for anabolic growth both require an electrochemical gradient across the mitochondrial inner membrane, produced as a result of redox reactions by the electron transport chain. In addition to driving ATP production, the proton gradient is required for passive and active transport of substrates, including pyruvate into the mitochondrial matrix, pumping of cations from matrix and transport of phosphate into the matrix. These processes are impeded by futile leak currents within the inner membrane. We are currently studying the role of ion leak channels in proliferation of glioblastoma multiforme cells.
Mitochondrial energetic efficiency in neuronal plasticity and degeneration
Numerous studies have linked mitochondria to the etiology of neurodegenerative conditions including Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). In recent years there has been growing evidence in support of the hypothesis that a contributing cause to neurodegeneration in these conditions is the failure of mitochondria to efficiently produce ATP to match cellular energy requirements during high neuronal activity or under stress conditions. We are interested in the molecular mechanisms underlying neuronal metabolic efficiency. We are currently investigating the function of mitochondrial metabolism in neurodegeneration in the genetic models of PD and ALS as well as modulation of mitochondrial leak currents for treatment of these conditions.
Pharmacological modulation of mitochondrial ion leak currents
We have developed a high-throughput assay for screening drugs and small molecules for negative and positive modulation of the mitochondrial proton leak currents. We are currently studying the role of a number of candidate compounds in the models of brain tumors and Parkinson’s disease.
Prediction of protein-protein interactions based on whole genome phylogenetic profiles
We have utilized a series of bioinformatics techniques including phylogenetic profiling and sequence analysis to study the evolution, protein-protein interaction and signaling pathways of mitochondrial proteins that may play a role in pathogenesis of cancer and neurodegenerative conditions. Based on the hypothesis that functionally related proteins are gained and lost together in evolution, phylogenetic profiling is used widely to predict protein complex subunits, signaling pathways and novel protein-protein interactions. The aim of this project is to construct a genome-wide structural/functional linkage network by performing a comprehensive phylogenetic profiling analysis across a wide range of eukaryotic and prokaryotic species