Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Abstract

Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

Mitofusins: from mitochondria to fertility

“…Another function of MAMs is to allow the exchange of Ca 2+ between two organelles (the ER and mitochondria) [ 57 , 80 ]. MAMs help to create a microregion of high Ca 2+ within the binding region of the ER and mitochondria that can enhance the transport of Ca 2+ to the mitochondria via mitochondrial calcium monomers [ 81 , 82 ]. This Ca 2+ uptake event via MAMs is essential for maintaining cellular bioenergetics, since this process also involves Krebs cycle regulation, dephosphorylation and the activation of pyruvate dehydrogenase [ 83 , 84 ].…”

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

“…The modulation of calcium flow from the endoplasmic reticulum to the mitochondria takes place through crosstalk modulated by the Mitochondria associated membranes (MAM). It determines the activation of IP3R (inositol 1,4,5-trisphosphate receptor) and VDAC (mitochondrial voltage-dependent anion channels) [ 82 ]. Specifically, following the stimulation of GPRC6A receptors and calcium-sensing receptor (CASr), both G-protein-coupled receptors (GPCRS), phospholipase C is activated.…”

The Potential of Small Molecules to Modulate the Mitochondria–Endoplasmic Reticulum Interplay in Alzheimer’s Disease

“…Indeed, blocking IP3Rs and MCU has been the most used strategies to influence Ca 2+ in this nanodomain (Gomez-Suaga et al, 2017;Naia et al, 2021a). This has been thoroughly reviewed in several publications (Magalhães Rebelo et al, 2020;Leal and Martins, 2021;Rodríguez et al, 2022). Briefly, various strategies can be implemented targeting the Ca 2+ shuttling bridge at MERCS:…”

“…Decreased activation of MCU and its components, however, have been shown to enhance neuronal damage in mouse neurons and fibroblasts (Verma et al, 2017). A recent review has thoroughly assessed how MERC-dependent MCU activation could be neuroprotective in models of neurodegeneration, highlighting molecules such as kaempferol as potential agents to prevent neurodegeneration (Rodríguez et al, 2022).…”