Cytosolic Ca(2+) gradients and mitochondrial Ca(2+) uptake in resting muscle fibers: A model analysis

Calcium ions (Ca(2+)) enter mitochondria via the mitochondrial Ca(2+) uniporter, driven by electrical and concentration gradients. In this regard, transgenic mouse models, such as calsequestrin knockout (CSQ-KO) mice, with higher mitochondrial Ca(2+) concentrations ([Ca(2+)](mito)), should display higher cytosolic Ca(2+) concentrations ([Ca(2+)](cyto)). However, repeated measurements of [Ca(2+)](cyto) in quiescent CSQ-KO fibers never showed a difference between WT and CSQ-KO. Starting from the consideration that fluorescent Ca(2+) probes (Fura-2 and Indo-1) measure averaged global cytosolic concentrations, in this report we explored the role of local Ca(2+) concentrations (i.e., Ca(2+) microdomains) in regulating mitochondrial Ca(2+) in resting cells, using a multicompartmental diffusional Ca(2+) model. Progressively including the inward and outward fluxes of sarcoplasmic reticulum (SR), extracellular space, and mitochondria, we explored their contribution to the local Ca(2+) distribution within the cell. The model predicts Ca(2+) concentration gradients with hot spots or microdomains even at rest, minor but similar to those of evoked Ca(2+) release. Due to their specific localization close to Ca(2+) release units (CRU), mitochondria could take up Ca(2+) directly from high-concentration microdomains, thus sensibly raising [Ca(2+)](mito), despite minor, possibly undetectable, modifications of the average [Ca(2+)](cyto).