Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions

Donato D'Angelo; Denis Vecellio Reane; Anna Raffaello

doi:10.3389/fmolb.2023.1336416

Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions

Front Mol Biosci. 2023 Dec 12:10:1336416. doi: 10.3389/fmolb.2023.1336416. eCollection 2023.

Authors

Donato D'Angelo¹, Denis Vecellio Reane^{1

2}, Anna Raffaello³

Affiliations

¹ Department of Biomedical Sciences, University of Padua, Padua, Italy.
² Institute for Diabetes and Obesity, Helmholtz Zentrum München, Munich, Germany.
³ Department of Biomedical Sciences, Myology Center (CIR-Myo), University of Padua, Padua, Italy.

Abstract

Ca²⁺ ions serve as pleiotropic second messengers in the cell, regulating several cellular processes. Mitochondria play a fundamental role in Ca²⁺ homeostasis since mitochondrial Ca²⁺ (mitCa²⁺) is a key regulator of oxidative metabolism and cell death. MitCa²⁺ uptake is mediated by the mitochondrial Ca²⁺ uniporter complex (MCUc) localized in the inner mitochondrial membrane (IMM). MitCa²⁺ uptake stimulates the activity of three key enzymes of the Krebs cycle, thereby modulating ATP production and promoting oxidative metabolism. As Paracelsus stated, "Dosis sola facit venenum,"in pathological conditions, mitCa²⁺ overload triggers the opening of the mitochondrial permeability transition pore (mPTP), enabling the release of apoptotic factors and ultimately leading to cell death. Excessive mitCa²⁺ accumulation is also associated with a pathological increase of reactive oxygen species (ROS). In this article, we review the precise regulation and the effectors of mitCa²⁺ in physiopathological processes.

Keywords: calcium; cell death; metabolism; mitochondria; mitochondrial calcium uniporter (MCU).

Publication types

Review

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported with funding from the Italian Ministry of University and Research (PRIN 20207P85MH to AR) and European Union (Next-Generation EU CN00000041). DV was supported by European Union HORIZON-MSCA-2021-PF 101065790.