Cardiac Calcium Signaling And Mitochondrial Metabolic Function

Mitochondrial calcium uptake is critically important in cellular function, energy production, and initiation of cell death. Even though the large flux of calcium can affect intracellular signals, the amount of calcium uptake by mitochondria is a topic of debate. Here we use computer simulations to study the effects of calcium sparks observed in cardiac myocytes on mitochondrial metabolic function, using the Virtual Cell platform (NIH grant # P41 GM103313). The simulations employ different 2D and 3D representations of crista geometry, including lamellar and tubular structures, variation in crista openings to the intermembrane space (between the inner boundary and outer membranes), and newly described fenestrations within cristae (that interconnect matrix compartments). Variable distribution of the mitochondrial calcium uniporter on the inner membrane is also used. Simulations suggest that mitochondrial crista geometry and orientation relative to spark source critically affect the diffusion of [Ca2+] in the intracristal spaces. Intracristal [Ca2+] exhibits more rapid changes than matrix [Ca2+] in response to changes in extramitochondrial [Ca2+]. The spark dynamics and the distribution of the mitochondrial calcium uniporter on the inner membrane also can significantly affect mitochondrial matrix [Ca2+]. By varying key parameters, the model can be used to predict the average level of matrix [Ca2+] during and after a spark event and its expected effect on respiration (e.g., activation of dehydrogenases) and adenine nucleotide levels in matrix and intracristal spaces. Extreme conditions leading to calcium overload and triggering of the permeability transition can also be explored and compared to experimental results. These modeling capabilities, that include cellular calcium signaling, metabolic characteristic of mitochondria, subcellular anatomy of calcium signaling, and nanoscale organization of mitochondria, can inform and provoke new future experiments. (Supported by NIH Grant U01HL116321)