We are interested in understanding the role of mitochondria in complex human diseases. Many would consider mitochondria as simple kidney bean-shaped organelles that just make ATP! On a closer look however, mitochondria are quite diverse in morphology, protein composition, and cellular functions across tissues and organisms.

The goal of our research is to critically evaluate how mitochondria engage in complex disease pathways and to identify ways to alter or restore mitochondrial function to avert disease progression. We use chemical and genetic screening tools to systematically interrogate disease pathways to understand how mitochondria fits into the overall disease picture.

We started our journey on the role of mitochondria in inflammatory pathway and uncovered the role of mitochondria in switch-like behavior of inflammatory activation. We find that mitochondrial perturbation alone do not lead to full disease pathway activation but rather require key interacting partners. We hope to continue our journey of mitochondria in the areas of neurodegenerative diseases and apply our findings in rare mitochondrial diseases.

The backbone of our research is to use chemicals as a tool to interrogate complex cellular systems. People often think of chemical screen in the context of target-based screen where one is interested in inhibiting or activating a known target.

We instead specialize in cell-based phenotypic screen in which we use cellular assays as a readout and search for chemicals that alter those assay values. The chemical hits then become experimental tool to systematically interrogate complex disease pathways (sometimes called chemical genetics approach). 

Rather than performing simple phenotypic screens, we perform multiple assays in parallel for the same set of compounds or generate matrix-based screening result consisting of activators and inhibitors of particular cellular process. By performing data-mining of these rich screening dataset, we uncover novel disease mechanisms, identify previously unknown target of chemicals,  and identify unexpected relationships between assay parameters, leading to new biology.

Mitochondria are constantly being exposed to environmental chemicals. Negative charge of mitochondrial matrix attracts positively charged chemicals such as ethidium bromide. Mitochondria have bacterial-like ribosome which are targeted by some antibiotics. Mitochondrial DNA polymerase is inhibited by nucleotide reverse transcriptase inhibitor (NRTI) in HIV medication, mitochondria are sensitive to cancer drugs such as doxorubicin which can bind to mitochondria-specific lipid called cardiolipin. In fact, mitochondrial toxicity is one of the most common causes of unexpected drug toxicity. Moreover, pesticide, fungicide, piscicide (fish poison) target mitochondrial oxidative phosphorylation (OXPHOS). 

Nanoparticles represent new class of potential hazard for mitochondria and are increasing being used for electronics, cosmetics, and medicine. Some nanoparticles, such as silver nanoparticles, are known to induce mitochondrial damage.

By using chemical genetics approach, we have uncovered new mitochondrial toxicity in pharmaceutical drugs, and identified mechanisms of toxicity for nanoparticles. We hope to design more sensitive assays to detect mitochondrial vulnerabilities and develop new strategies to analyze mechanisms of mitochondrial toxicity.

Progress in new omics technologies provide rich source of data for uncovering signatures of complex human diseases. While these datasets provide insights into novel disease mechanisms, the disease signature from these datasets can also be converted directly into cell-based high-throughput screening assays.

Our first gene expression-based screen used gene expression signature of type 2 diabetes patients, which led to identification of natural products involved in OXPHOS activation (Nat Biotechnol 2008).

We continue to participated in analysis of omics dataset for complex human diseases. Today, the vast amounts of data for transcriptome, proteome, metabolome, microbiome, and detailed disease phenotyping are all combined together to generate deep phenotyping. We participated in deep phenotyping studies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and insulin resistance. We hope to continue mining human datasets for novel disease hypothesis and for developing new cell-based assays for drug screens.