Miller Lab

Decoding the subcellular organization of metabolism

Cells have specialized compartments where metabolic reactions are safely partitioned, ensuring efficient metabolic turnover and preventing undesirable cross-reactions. However, the dynamic intracellular spatial and temporal coordination of metabolic pathways that are essential in maintaining cell functions are not well defined. Recent discoveries have challenged traditional beliefs that glycolysis occurs on the cytosol and the citric acid cycle happens in mitochondria, revealing that selected metabolic enzymes venture into the cell's control center, the nucleus (Image 1).

Our research focuses on exploring the world of metabolic processes in the nucleus and how they support vital cellular functions: Cell division, transcriptional regulation, and epigenetic modifications. As a model system, we use the liver’s remarkable regenerative potential to understand how metabolic activity in the nucleus can support cell proliferation. The liver is the only organ in the human body that can largely regenerate and surgical hepatectomy is a common treatment option for various liver diseases. In mice, this process takes about 3 days which makes this model an excellent choice to study the nuclear processes that accompany rapid cell division (Image 2). In contrast to chronic liver diseases, where the liver must regenerate over long periods of time, healthy liver regeneration is completed after a couple of days and the cells return to their homeostatic resting state.

We use a combination of in vivo physiology, advanced imaging, molecular biology, stable isotope tracer methodology and integrative multi-omics approaches, to define the critical nuclear metabolic pathways that enable liver regeneration processes and how these mechanisms are disrupted in liver disease. We seek to create a collaborative and multidisciplinary research environment and use clinically relevant model systems to bridge the gap between fundamental research and its potential application in clinical settings.