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

Lorenzo Marcucci; Antonio Michelucci; Carlo Reggiani

doi:10.1016/j.bpr.2023.100117

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

Biophys Rep (N Y). 2023 Jul 17;3(3):100117. doi: 10.1016/j.bpr.2023.100117. eCollection 2023 Sep 13.

Authors

Lorenzo Marcucci^{1

2}, Antonio Michelucci³, Carlo Reggiani^{1

4}

Affiliations

¹ Department of Biomedical Sciences, University of Padova, Padova, Italy.
² Center for Biosystems Dynamics Research, RIKEN, Suita, Japan.
³ Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy.
⁴ Science and Research Center Koper, Institute for Kinesiology Research, Koper, Slovenia.

Abstract

Calcium ions (Ca²⁺) enter mitochondria via the mitochondrial Ca²⁺ uniporter, driven by electrical and concentration gradients. In this regard, transgenic mouse models, such as calsequestrin knockout (CSQ-KO) mice, with higher mitochondrial 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⁺ distribution 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 undetectable, modifications of the average [Ca²⁺]_cyto.