Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins
Abstract
:1. Introduction
2. Calcium Transport Systems in Mitochondria
2.1. Calcium Influx and Efflux through OMM
2.2. Calcium Influx through IMM
2.2.1. Calcium Influx by Mitochondrial Ca2+ Uniporter (MCU) Multi-Protein Complex
2.2.2. Rapid Mode Mechanism (RaM) of Ca2+ Uptake
2.2.3. The Mechanism of Ca2+ Uptake Requiring Mitochondrial Ryanodine Receptor (mRyR)
2.2.4. The Mechanism of Ca2+ Uptake Including LETM1
2.3. Calcium Efflux through IMM
2.3.1. The Mechanism of Ca2+ efflux by NCLX
2.3.2. The Mechanism of Ca2+ Efflux by HCX
2.3.3. The Mechanism of Ca2+ Efflux by LETM1
2.3.4. The Mechanism of Ca2+ Efflux by mPTP/mPTPC
3. The Family of Bcl-2 Proteins
3.1. Anti-Apoptotic Bcl-2 Proteins
3.2. Pro-Apoptotic Bcl-2 Proteins
3.3. BH3-Only Bcl-2 Proteins
3.4. Interactions between Bcl-2 Proteins
4. Regulation of Mitochondrial Ca2+ Transport Systems by Bcl-2 Proteins
4.1. Bcl-2 Proteins and Ca2+ Influx through VDAC
4.2. Bcl-2 Proteins and Na+/Ca2+ Exchangers
4.3. Bcl-2 Proteins and mPTP (See Also Section Calcium Efflux through mPTPC)
5. Regulation of Cell Death by Mitochondrial Transport of Calcium and Bcl-2 Proteins
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ATP | adenosine triphosphate |
Bcl-2 | B-cell lymphoma-2 |
TCA | tricarboxylic acid |
MOMP | mitochondrial outer membrane permeabilization |
NADH | nicotinamide adenine dinucleotide |
IMM | inner mitochondrial membrane |
IMS | intermembrane space |
OMM | outer mitochondrial membrane |
MCU | mitochondrial Ca2+ uniporter |
CC-domains | coiled-coil domains |
mRyR | mitochondrial ryanodine receptor |
RaM | rapid mode of Ca2+ uptake |
LETM1 | leucine zipper- EF-hand containing transmembrane protein |
ETC | electron transport chain |
NCX | Na+/Ca2+ exchanger |
NCLX | Na+/Ca2+/Li+ exchanger |
HCX | H+/Ca2+ exchanger |
mPTPC | mitochondrial permeability transition pore complex |
mPTP | mitochondrial permeability transition pore |
ANT | adenine nucleotide translocator |
CypD | cyclophilin D |
PiC | phosphate carrier |
VDAC | voltage-dependent anion channel |
MCUb | mitochondrial Ca2+ uniporter dominant negative beta subunit |
EMRE | essential MCU regulatory element |
MICU | mitochondrial Ca2+ uptake protein |
MCUR1 | mitochondrial Ca2+ uniporter regulator 1 |
RaM | RApid mode of Ca2+ uptake |
SLC25A23 | solute carrier 25A23 |
mRyR | mitochondrial ryanodine receptor |
PiC | phosphate carrier |
SPG7 | m-AAA protease Spastic Paraplegia 7 |
Mff | mitochondrial fission factor |
BH domains | Bcl-2 homology domains |
Bcl-XL | Bcl-extra long |
Mcl-1 | myeloid cell leukemia-1 |
Bcl-w | Bcl-2-like protein 2 |
BFL-1/A1 | Bcl-2-related protein A1 |
BIM | Bcl-2-like 11 |
BID | BH3 interacting domain death agonist |
PUMA | p53-upregulated modulator of apoptosis |
NOXA | phorbol-12-myristate13-acetate-induced protein 1 |
BAD | Bcl-2-associated agonist of cell death |
BIK | Bcl-2 interacting killer |
HRK | Harakiri protein |
HRK/DP5 | Harakiri protein/Bcl-2 interacting protein death protein 5 |
BMF | Bcl-2 modifying factor |
SMAC | second mitochondria-derived activator of caspase |
DIABLO | direct IAP binding protein with low pI |
HtrA2 | high temperature requirement protein A2 |
Mfn | mitofusin |
ROS | reactive oxygen species |
RCD | regulated cell death |
PCD | programmed cell death |
ADCD | autophagy-dependent cell death |
ICD | immunogenic cell death |
LDCD | lysosome-dependent cell death |
ER | endoplasmic reticulum |
SR | sarcoplasmic reticulum |
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Direction of Ca2+ Transport | Mitochondrial Membrane Through Which Ca2+ Transport is Realized | The System Responsible for Ca2+ Transport | Characteristic Features of the Transport System | Regulation of Mitochondrial Ca2+ Transport Systems by Bcl-2 Proteins |
---|---|---|---|---|
Ca2+ influx | OMM | VDAC | The main transport system for metabolites, cations, and anions across OMM. It serves as a contact point between the OMM and IMM [42]; 3 different VDAC isoforms have been identified [45,48,53,60] | Ca2+ influx via VDAC is regulated by Bcl-2, Bcl-XL and Mcl-1 [29,254,255,256,257,260,263] |
IMM | MCU | MCU is the major pathway of the mitochondrial Ca2+ uptake [9,17,60,63,64,65]. MCU consists of several subunits (see Box 2 for details [65,66,68,69,70] | Activity of MCU is mediated by Bcl-2 proteins (BID, BAD, Bcl-XL) [194]. | |
RaM | RaM accumulates Ca2+ with the kinetics hundreds of times faster than MCU. It could also represent a different form or substrate of MCU [89,91] | |||
mRyR (mitochondrial ryanodine receptor) | The isoform of RyR1. Proposed as a Ca2+-influx system, involved in the regulation of Ca2+ efflux under mitochondrial Ca2+ overload [92,93] | |||
LETM1 | Proposed as Ca2+/H+ antiporter, also involved in the K+/H+ exchange. Shares a key role with MCU in catalyzing Ca2+ uptake into mitochondria [62,96,101,103] | |||
Ca2+ efflux | OMM | VDAC | See above | See above |
mPTP pore complex | ANT, PiC and CypD serve as mPTP regulators in the IMM. The F1F0ATP synthase has been suggested as pore-forming unit in the IMM [110,135,138,141,144,148] | Activity of mPTPC is mediated by the ensemble of Bcl-2 proteins (Bax/Bak, BID, BAD, Bcl-XL) [255,258,259,261] | ||
IMM | (NCLX) Na+/Ca2+/Li+ exchanger | Na+-dependent Ca2+ transport also includes the transport of Li+. It is typical for excitable tissues (brain, heart) [113,114]. | Bcl-2 protein can modulate the activity of NCLX [264]. | |
HCX (H+/Ca2+ exchanger) | Na+-independent Ca2+ efflux is dominant in the non-excitable tissues (liver, kidney, lung, smooth muscle) [119,126] | |||
LETM1 | Proposed as an alternative mechanism for the regulation of Ca2+ release and functions as a Ca2+/H+ antiporter during specific conditions [62,96,101,102,103] | |||
mPTP pore complex | See above | See above |
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Naumova, N.; Šachl, R. Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins. Membranes 2020, 10, 299. https://doi.org/10.3390/membranes10100299
Naumova N, Šachl R. Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins. Membranes. 2020; 10(10):299. https://doi.org/10.3390/membranes10100299
Chicago/Turabian StyleNaumova, Natalia, and Radek Šachl. 2020. "Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins" Membranes 10, no. 10: 299. https://doi.org/10.3390/membranes10100299
APA StyleNaumova, N., & Šachl, R. (2020). Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins. Membranes, 10(10), 299. https://doi.org/10.3390/membranes10100299