Projects

In heart muscle cells, calcium regulates cells' contraction and mitochondria energy production needed to perform mechanical work and maintain ion balance. The primary calcium source in adult mammalian cells is the sarcoplasmic reticulum (SR). Recently, it has been shown that SR and mitochondria are physically linked and regulate mitochondrial respiration. The precise interaction between them is essential for maintaining energy balance in the heart, yet many aspects of this regulatory pathway are still poorly understood. This project aims to unravel mechanistic aspects of SR-mitochondria interaction by taking advantage of structural and functional changes in heart muscle cells during development and in disease. We expect this knowledge to be applicable at the other end of the heart physiology spectrum – disease, as failing hearts resemble in many ways the hearts from early stages of development.

In heart muscle cells, energy is transferred from mitochondria to multiple locations in the cell, where it is utilized to perform mechanical work and maintain ion balance. On the molecular diffusion pathway, several intracellular structures impose restrictions, which are prominent in healthy cells and, some data suggests, disappear in disease. While the restrictions and some clinical data point towards a major role of creatine kinase (CK) assisted energy transfer in the cell, data from loss-of-function animal models are equivocal. In this project, we will develop and use state-of-the-art experimental and mathematical modeling approaches to characterize the diffusion environment within cardiomyocytes and quantify the role of CK in the healthy heart. By identifying the adaptations in transgenic mice, we expect to identify new treatment targets for heart failure patients with reduced CK flux.