Our Research (WORKS)
The ultimate goal of our research is to understand the process that promotes cardiomyocyte injury or loss that eventually leads to cardiac dysfunction and heart failure.
Organelle Communication: Mitochondria-Lysosome Interactions
Recent technological advances have revealed that organelles communicate by contacting, forming micro-environments, or exchanging components for coordinated inter-organelle signal transduction. As a new project, we are observing "Organelle communication", particularly the communication between lysosomes and mitochondria, to understand its biological meaning. As a model, we monitor changes in the behavior of lysosomes and mitochondria caused by the cardiotoxicity of the anticancer drug Doxorubicin using live imaging.
Live Imaging Movie: Mitochondria-Lysosome Interaction under Doxorubicin stress
Real-time monitoring of mitochondrial (green) and lysosomal (magenta) interactions during exposure to doxorubicin.
1a. Live Imaging of Lysosome-Mitochondria Dynamics under Doxorubicin Cardiotoxicity
We use high-resolution live imaging to track real-time physical interactions and dynamics between mitochondria and lysosomes in cardiomyocytes. By exposing cells to doxorubicin, we can observe how cardiotoxicity alters their communication channels and organelle behavior.
1b. Inter-Organelle Quality Control Mechanisms
We study how lysosomes and mitochondria coordinate their quality control pathways (such as mitophagy) to defend against drug-induced cardiac stress, and whether rescuing these communication pathways can prevent cardiomyocyte death.
Lysosomal Dysfunction in the Diabetic Heart
We are investigating the pathological significance of Lysosomal Membrane Permeabilization (LMP) and Cathepsin D (CTSD) in diabetic heart injury using pharmacological and genetic gain- and loss-of-function approaches in both in vitro cultured cells and in vivo mouse models. Successful completion of this project will provide novel insight into the mechanisms that mediate diabetic cardiac injury, thus facilitating drug design for preventing or treating cardiomyopathy and heart failure in diabetes.
2a. Evaluate the level of lysosomal injury
“Physician, heal thyself”. Lysosomes, the ER physician in cells, do. There is a way to repairing or fixing damaged lysosomes. They can take care of themselves while they are also maintaining the other parts of cell. But, once the job is overwhelmed, this lysosome-based cellular healthcare system easily falls. So far, we have no good panel to monitor the health condition of lysosome itself. We are trying to develop a comprehensive review panel/index for evaluating the health condition of lysosomes (such as the structure, size, number, biogenesis, LMP, intracellular distribution, kinetics of lysosomal degradation) under various stresses.
2b. How to protect the lysosomes
We are seeking ways to limit or to repair LMP. There are some ways such as strengthening the lysosome membrane, or backing up the hole of injury. There are some candidates (drugs and genes) that potentially protect lysosomes. The beneficial effect and the optimal application requirements are currently under investigation. There is Plan B. Diabetes is a slow death process. So, lysosomes don’t know they’re in danger like boiling frogs. What if we give a shock to wake them up and get them ready to react to the sneaking stress? This plan B might sound counterintuitive, but this may be more effective like taking a vaccine shot for training your body defense system even before the situation gets more serious. We have some ideas for giving a minimal but sufficient shock to wake the lysosomes. The concept should be tested in culture dish and a practical way will be designed in the near future.