M.Sc Thesis

M.Sc StudentKamoun David
SubjectQuantifying Mitochondrial 3D-Deformations in Cardiomyocytes
to Assess the Structural Anisotropy and Energetics
DepartmentDepartment of Biomedical Engineering
Supervisor ASSOCIATE PROF. Yael Yaniv
Full Thesis textFull thesis text - English Version


Introduction: In the heart, mitochondria are arranged in pairs sandwiched between contractile machinery, which is the major ATP consumer. Thus, in response to the contraction-relaxation cycle of the contractile machinery, the mitochondrial membrane should deform accordingly. Recent works have shown that deformations on the membrane surrounding isolated ATP synthesis affect its rate and, in isolated mitochondria, those membranal deformations affect the mitochondrial membrane potential. However, it is unknown whether physiological deformation of the mitochondrial membrane in response to the contraction-relaxation cycle can act as a bioenergetic signaling mechanism between ATP demand to supply.

Methods: We developed a new system to measure mitochondrial 2D deformations in single cell that is contracting against different external loads. To reveal the role of mitochondrial 3D deformation in cardiac energetics, we developed a novel biophysical model that includes a description of ionic molecules on the mitochondrial membrane, Ca2 cycling, and mitochondrial membrane stress. The input to the model, the mitochondrial 3D deformation measured in unloaded rat cardiac myocytes, is converted to stress by the Navier-Lamé equation. The stress effect on the mitochondrial membrane potential (assuming that the mitochondrial membrane behaves as a capacitor), the stretch-activated channels, and the stress effect on ATP synthase rate are affecting mitochondrial membrane potential.

Results: The steady state sarcomere and mitochondrial lengths and mitochondrial width was design. The model faithfully reproduces the experimentally measured mitochondrial contraction in the longitudinal axis and mitochondrial expansion in the radial 2D axes. The model predicts that, in response to the mitochondrial 3D deformation, the stress on the mitochondria will be in the order of MPa, with changes in the order of tens of kPa around the mean. In response to these changes, the mitochondrial membrane potential will changes by ~0.5mV, with small but significant changes in the ATP production rate during the contraction-relaxation cycle.

Conclusions: While bioenergetic feedback between heart cell contractile machinery and mitochondrial 3D deformations does exist, mitochondrial 3D deformation dynamics in unloaded cells is not the major feedback mechanism between the ATP consumers and the ATP synthase function.