For decades, mitochondria have been primarily viewed as biosynthetic and bioenergetic organelles generating metabolites for the production of macromolecules and ATP, respectively. Dr. Chandel’s work has elucidated that mitochondria have a third distinct role whereby they participate in cellular signaling processes through the release of reactive oxygen species (ROS) and metabolites independent of ATP and macromolecule production. Our work has implicated the necessity of mitochondrial ROS for multiple biological processes including hypoxic activation of HIFs, cellular differentiation, and adaptive immunity. Previously, the dogma in the field had been that mitochondrial ROS are only produced in pathological settings to cause both lipid, protein and DNA damage. However, our work demonstrates that mitochondrial ROS are utilized as messengers to maintain normal biological and physiological functions. Our studies suggest that the current widespread use of antioxidants is likely to be detrimental rather than beneficial for alleviating a myriad of diseases as this could interfere with normal physiological processes. Recently, our work has shown that mitochondria release the metabolite L-2HG, which increases histone and DNA methylation to control hematopoietic stem cell (HSC) differentiation and regulatory T cell (Treg) function, respectively. In summary, our lab has been instrumental in changing our view of mitochondria from the “powerhouses" of cell to “signaling organelles”. Beyond metabolites and ROS, there are multiple ways mitochondria function as signaling organelles (see figure).
In the field of cancer, our work was the first to genetically demonstrate the necessity of mitochondrial respiratory chain is necessary for tumor growth and angiogenesis in vivo. Our recent work points to key role of the respiratory chain in supporting biomass of cancer cells needed for in vivo tumor growth. These findings were seminal for the cancer metabolism field since the 1920s the prevailing idea was that only increased aerobic glycolysis (i.e. the Warburg Effect) was the dominant metabolic reprogramming event in cancer cells and endothelial cells. Another key finding in the lab was genetically elucidating that the anti-diabetic drug metformin prevents tumorigenesis by inhibiting mitochondrial complex I within cancer cells. Finally, our work provided a conceptual model whereby mitochondria generated ROS can trigger local signaling events in the cells to promote growth but can be elevated to levels that are detrimental. Thus, tumor cells increase their antioxidant capacity to prevent ROS induced cell death. Our current projects involve the use of CRISPR based genetic screens to uncover metabolic vulnerabilities in the presence of standard care of therapy.
Viral pneumonia is currently among the most common causes of death in the world. Viral pneumonia impairs tissue repair leading to both in-hospital death and prolonged hospital-acquired disability. Two leading causes of viral pneumonia are influenza A virus and SARS-CoV-2 virus. We use mouse models to test whether metabolism can modulate inflammation, host defense and repair to the lungs upon exposure to influenza A virus.
Metformin is a biguanide drug that boosts healthspan in multiple model organisms and humans. Metformin in humans is used as the first-line therapy for type II diabetes. In addition, metformin has anti-tumor and anti-inflammatory effects which likely contribute to its geroprotective activity. Currently, the TAME trial will test whether metformin can delay age-related chronic diseases in humans. However, metformin’s the direct mechanism of action is poorly understood. The mechanism of metformin action must be considered at two levels: (1) the molecular target of metformin and (2) the therapeutic pathways triggered by metformin acting on its molecular target in different cell types. A leading hypothesis is that metformin inhibits mitochondrial complex I (NADH dehydrogenase) to exert anti-aging effects. Currently, we are using genetic models to determine the essentiality of mitochondrial complex I inhibition in gut epithelium, hepatocytes, and immune cells for metformin to exert its anti-diabetic and anti-inflammatory effects.
Neurological diseases including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer disease (AD) have all been linked to metabolic dysregulation. We are using mouse models and IPSCs to test whether metabolic dysfunction is a causal agent rather than a hallmark of these diseases. This work is complemented by our work on primary mitochondrial disease mouse models that manifest neurological symptoms.