Cytosolic Ca gradients and mitochondrial Ca uptake in resting muscle fibers: A model analysis.

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