Cytosolic Ca2+ gradients and mitochondrial Ca2+ uptake in resting muscle fibers: A model analysis

Calcium ions (Ca2+) enter mitochondria via the mitochondrial Ca2+ uniporter, driven by electrical and concentra-tion gradients. In this regard, transgenic mouse models, such as calsequestrin knockout (CSQ-KO) mice, with higher mitochon-drial Ca2+ concentrations ([Ca2+]mito), should display higher cytosolic Ca2+ concentrations ([Ca2+]cyto). However, repeated measurements of [Ca2+]cyto in quiescent CSQ-KO fibers never showed a difference between WT and CSQ-KO. Starting from the consideration that fluorescent Ca2+ probes (Fura-2 and Indo-1) measure averaged global cytosolic concentrations, in this report we explored the role of local Ca2+ concentrations (i.e., Ca2+ microdomains) in regulating mitochondrial Ca2+ in resting cells, using a multicompartmental diffusional Ca2+ model. Progressively including the inward and outward fluxes of sarcoplasmic reticulum (SR), extracellular space, and mitochondria, we explored their contribution to the local Ca2+ distribu-tion within the cell.The model predicts Ca2+ concentration gradients with hot spots or microdomains even at rest, minor but similar to those of evoked Ca2+ release. Due to their specific localization close to Ca2+ release units (CRU), mitochondria could take up Ca2+ directly from high-concentration microdomains, thus sensibly raising [Ca2+]mito, despite minor, possibly unde-tectable, modifications of the average [Ca2+]cyto.