Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?
Abstract
:1. Introduction
2. MAMs’ Composition and Function
3. Ca2+ Regulates Mitochondrial Functions
- The first is distribution, because clustered mitochondria are able to buffer Ca2+ more efficiently than disperse mitochondria. Mitochondrial fusion/fission events require elevated amounts of cytosolic Ca2+ to be transferred to the mitochondria [33,55]. In this way, Ca2+ can activate the cytosolic GTPase dynamin-related protein (Drp-1), which is recruited to form a ring around mitochondria to promote mitochondrial fission [31]. On the other hand, mitofusin 2 (MFN2), the GTPase responsible for the OMM fusion, also participates as a key regulator of MAMs, contributing to intracellular Ca2+ homeostasis [33].
- Connectivity, because elongated mitochondria are better Ca2+ conductors, distributing the cation along the fused network. It has been described that, while fragmented mitochondria buffer Ca2+ from the ER in a heterogeneous manner, tubular mitochondria incorporate Ca2+ in an equilibrated and connected way [54,56].
- Vicinity is a dynamic property that also affects Ca2+ buffering, since elevated concentrations of Ca2+ near mitochondria are required to promote mitochondrial Ca2+ uptake. In this context, Csordás et al. demonstrated the importance of spacing distance in MAMs for an efficient Ca2+ transfer, outlining that it is essential that the tethered bridge is properly assembled to ensure Ca2+ influx into the mitochondria [44,57].
4. Ca2+ and Oxidative Stress
5. MAMs’ Communication and Neurological Diseases
6. Therapeutic Approaches Targeting MAMs
6.1. Sigma-1 Receptor as a Therapeutic Target
6.1.1. Pridopidine
6.1.2. SA4503
6.1.3. Blarcamesine
6.1.4. PRE-084
6.1.5. Fluvoxamine
6.2. Mitochondrial Calcium Uniporter as a Therapeutic Target
Kaempferol
6.3. Other Approaches
6.3.1. Taurine
6.3.2. Nerve Growth Factor
6.3.3. MiCUps
6.3.4. Antioxidants
7. Conclusions and Future Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
AD—Alzheimer’s disease | ALS—Amyotrophic lateral sclerosis |
Bcl-2—B-cell lymphoma 2 | BiP/GRP78—Binding immunoglobulin protein/Glucose response protein 78 |
Ca2+—Calcium | CMT—Charcot–Marie–Tooth |
Drp-1—Dynamin -related protein | EMRE—Essential MCU regulator |
FRDA—Friedreich’s ataxia | GDAP1—Ganglioside-induced associated protein 1 |
GRP75—Glucose-regulated protein 75 | GSH—Glutathione |
H2O2—Hydrogen peroxide | HD—Huntington’s disease |
IMM—Inner mitochondrial membrane | IP3R—Inositol 1,4,5-trisphosphate receptor |
MAMs—Endoplasmic reticulum–mitochondria-associated membranes | MCU/Mcu—Mitochondrial calcium uniporter |
MCUb—Mitochondrial calcium uniporter regulatory subunit | MCUR1—Mitochondrial calcium uniporter regulator 1 |
MFN2—Mitofusin 2 | MICU1/2/3—Mitochondrial calcium uptake protein 1, 2, 3 |
MiCUps—Mitochondrial Ca2+ uptake enhancers | NGF—Nerve Growth Factor |
NRF2—Nuclear factor erythroid 2-related factor 2 | OMM—Outer mitochondrial membrane |
PD—Parkinson’s disease | ROS—Reactive oxygen species |
RyR—Ryanodine receptor | SCA2/3—Spinocerebellar ataxias type 2 and 3 |
Sig-1R—Sigma non-opioid intracellular receptor 1 | SOD1—Superoxide dismutase 1 |
SOD2—Superoxide dismutase 2 | SR/ER—Sarcoplasmic/endoplasmic reticulum |
VDAC—Voltage-dependent anion channel |
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Rodríguez, L.R.; Lapeña-Luzón, T.; Benetó, N.; Beltran-Beltran, V.; Pallardó, F.V.; Gonzalez-Cabo, P.; Navarro, J.A. Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases? Antioxidants 2022, 11, 165. https://doi.org/10.3390/antiox11010165
Rodríguez LR, Lapeña-Luzón T, Benetó N, Beltran-Beltran V, Pallardó FV, Gonzalez-Cabo P, Navarro JA. Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases? Antioxidants. 2022; 11(1):165. https://doi.org/10.3390/antiox11010165
Chicago/Turabian StyleRodríguez, Laura R., Tamara Lapeña-Luzón, Noelia Benetó, Vicent Beltran-Beltran, Federico V. Pallardó, Pilar Gonzalez-Cabo, and Juan Antonio Navarro. 2022. "Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?" Antioxidants 11, no. 1: 165. https://doi.org/10.3390/antiox11010165
APA StyleRodríguez, L. R., Lapeña-Luzón, T., Benetó, N., Beltran-Beltran, V., Pallardó, F. V., Gonzalez-Cabo, P., & Navarro, J. A. (2022). Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases? Antioxidants, 11(1), 165. https://doi.org/10.3390/antiox11010165