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Cited by 1,546Redox biology and oxidative stressCalcium signaling and nucleotide metabolismIon Channels and Receptors

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Calcium and ROS: A mutual interplay

Open access
Görlach, Agnes, Bertram, Katharina, Hudecova, Sona, Krizanova, Olga·2015·Redox Biology
DOI 10.1016/j.redox.2015.08.010PMC PMC4556774
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Abstract

Calcium is an important second messenger involved in intra- and extracellular signaling cascades and plays an essential role in cell life and death decisions. The Ca(2+) signaling network works in many different ways to regulate cellular processes that function over a wide dynamic range due to the action of buffers, pumps and exchangers on the plasma membrane as well as in internal stores. Calcium signaling pathways interact with other cellular signaling systems such as reactive oxygen species (ROS). Although initially considered to be potentially detrimental byproducts of aerobic metabolism, it is now clear that ROS generated in sub-toxic levels by different intracellular systems act as signaling molecules involved in various cellular processes including growth and cell death. Increasing evidence suggests a mutual interplay between calcium and ROS signaling systems which seems to have important implications for fine tuning cellular signaling networks. However, dysfunction in either of the systems might affect the other system thus potentiating harmful effects which might contribute to the pathogenesis of various disorders.

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Crossref · 10.1016/j.redox.2015.08.010

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Graphical abstract CC BY-NC-ND · PubMed Central
Fig. 1 Membrane transporters of calcium ions localized in the plasma membrane, the endoplasmic reticulum and in mitochondrial membranes. Calcium channels (illustrated by green boxes) transport calcium ions into the cytoplasm upon changes in membrane potential or ligand binding. Calcium pumps (yellow boxes) transport calcium from the cytoplasm or into the endoplasmic reticulum (ER) and are energy-dependent. Sodium–calcium exchangers belong to antiporters transporting calcium ions against sodium ions. Two receptors that are localized in the ER release calcium from the ER store. In mitochondria, calcium transport is realized through the mitochondrial permeability transition pore, mitochondrial uniporter and sodium calcium exchanger. Abbreviations: NCX – sodium-calcium exchanger; VDCC – voltage-dependent calcium channel; PMCA – plasma membrane calcium ATPase; ROC – receptor operated channels; TRPC – transient receptor potential channel; SERCA – sarco/endoplasmic reticulum calcium ATPase; RyR – ryanodine receptor; IP3R – inositol 1,4,5-trisphosphate receptor; mPTP – mitochondrial permeability transition pore; MCU – mitochondrial uniporter.
Fig. 1 Membrane transporters of calcium ions localized in the plasma membrane, the endoplasmic reticulum and in mitochondrial membranes. Calcium channels (illustrated by green boxes) transport calcium ions into the cytoplasm upon changes in membrane potential or ligand binding. Calcium pumps (yellow boxes) transport calcium from the cytoplasm or into the endoplasmic reticulum (ER) and are energy-dependent. Sodium–calcium exchangers belong to antiporters transporting calcium ions against sodium ions. Two receptors that are localized in the ER release calcium from the ER store. In mitochondria, calcium transport is realized through the mitochondrial permeability transition pore, mitochondrial uniporter and sodium calcium exchanger. Abbreviations: NCX – sodium-calcium exchanger; VDCC – voltage-dependent calcium channel; PMCA – plasma membrane calcium ATPase; ROC – receptor operated channels; TRPC – transient receptor potential channel; SERCA – sarco/endoplasmic reticulum calcium ATPase; RyR – ryanodine receptor; IP3R – inositol 1,4,5-trisphosphate receptor; mPTP – mitochondrial permeability transition pore; MCU – mitochondrial uniporter.CC BY-NC-ND · PubMed Central
Fig. 2 Calcium and ROS crosstalk between endoplasmic reticulum and mitochondria. The endoplasmic reticulum (ER) is a major site of calcium storage. Calcium from ER cisternae is flowing mainly through calcium release channels as inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR). These channels are accumulated in mitochondrial associated membranes (MAMs), which associate with the mitochondrial outer membrane. Calcium ions from the cytoplasm enter the mitochondria through voltage dependent anion channels (VDAC) or calcium uniporter. High levels of calcium stimulate respiratory chain activity leading to higher amounts of reactive oxygen species (ROS). ROS can further target ER-based calcium channels leading to increased release of calcium and further increased ROS levels. Increased ROS and calcium load can open the mitochondrial permeability transition pore (mPTP) resulting in the release of pro-apoptotic factors. Abbreviations: SERCA – sarco/endoplasmic reticulum Ca2+ ATPase; RyR – ryanodine receptors; IP3R – IP3 receptor; VDAC – voltage-dependent anion channel; ANT – adenine-nucleotide transporter; mPTP – mitochondrial permeability transition pore; mNCX – mitochondrial sodium/calcium exchanger.
Fig. 2 Calcium and ROS crosstalk between endoplasmic reticulum and mitochondria. The endoplasmic reticulum (ER) is a major site of calcium storage. Calcium from ER cisternae is flowing mainly through calcium release channels as inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR). These channels are accumulated in mitochondrial associated membranes (MAMs), which associate with the mitochondrial outer membrane. Calcium ions from the cytoplasm enter the mitochondria through voltage dependent anion channels (VDAC) or calcium uniporter. High levels of calcium stimulate respiratory chain activity leading to higher amounts of reactive oxygen species (ROS). ROS can further target ER-based calcium channels leading to increased release of calcium and further increased ROS levels. Increased ROS and calcium load can open the mitochondrial permeability transition pore (mPTP) resulting in the release of pro-apoptotic factors. Abbreviations: SERCA – sarco/endoplasmic reticulum Ca2+ ATPase; RyR – ryanodine receptors; IP3R – IP3 receptor; VDAC – voltage-dependent anion channel; ANT – adenine-nucleotide transporter; mPTP – mitochondrial permeability transition pore; mNCX – mitochondrial sodium/calcium exchanger.CC BY-NC-ND · PubMed Central
Fig. 3 ROS and calcium crosstalk can induce ER stress. In the course of oxidative protein folding in the endoplasmic reticulum (ER), reactive oxygen species (ROS) are generated during electron transfer between protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin-1 (ERO1α). PDI can also associate with ROS-generating NADPH oxidases (NOX), further increasing ROS levels in the ER. NOX-derived ROS can modulate SERCA activity thus increasing ER calcium levels, contribute to ER stress and activate the unfolded protein response (UPR). ROS increase calcium release to the mitochondria which activates ROS generation in the mitochondrial respiratory chain. Mitochondrial ROS can affect NOX thus further increasing ROS and calcium load in the ER resulting in a vicious circle ultimately leading to apoptosis. Abbreviations: SERCA – sarco/endoplasmic reticulum Ca2+ ATPase; MAM – mitochondria-associated ER membranes; NOX NADPH oxidase; PDI – protein disulfate isomerase; ERO1α – endoplasmic reticulum oxidoreductin-1.
Fig. 3 ROS and calcium crosstalk can induce ER stress. In the course of oxidative protein folding in the endoplasmic reticulum (ER), reactive oxygen species (ROS) are generated during electron transfer between protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin-1 (ERO1α). PDI can also associate with ROS-generating NADPH oxidases (NOX), further increasing ROS levels in the ER. NOX-derived ROS can modulate SERCA activity thus increasing ER calcium levels, contribute to ER stress and activate the unfolded protein response (UPR). ROS increase calcium release to the mitochondria which activates ROS generation in the mitochondrial respiratory chain. Mitochondrial ROS can affect NOX thus further increasing ROS and calcium load in the ER resulting in a vicious circle ultimately leading to apoptosis. Abbreviations: SERCA – sarco/endoplasmic reticulum Ca2+ ATPase; MAM – mitochondria-associated ER membranes; NOX NADPH oxidase; PDI – protein disulfate isomerase; ERO1α – endoplasmic reticulum oxidoreductin-1.CC BY-NC-ND · PubMed Central

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Authors
Görlach, A., Bertram, K., Hudecova, S., & Krizanova, O.
Affiliations
  • German Centre for Cardiovascular Research (DE)
  • Deutsches Herzzentrum München (DE)
Corresponding author
Görlach, Agnes
ORCID
Görlach, Agnes
Venue
Redox Biology
Publisher
Elsevier BV
Published
2015-12
Volume
6
Pages
260-271
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2015.08.010
PMC
PMC4556774
OpenAlex
W1165140024
Cited by
1,546
References
180
Citations by year
2026: 128 · 2025: 188 · 2024: 195 · 2023: 184 · 2022: 177 · 2021: 179 · 2020: 141 · 2019: 133 · 2018: 115 · 2017: 72 · 2016: 30 · 2015: 3
FWCI
7.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion)
Funders
  • Bundesministerium für Bildung und Forschung (SAV 2/0074)
  • Deutsches Zentrum für Herz-Kreislaufforschung
  • Deutsche Forschungsgemeinschaft (DFG-GO709/4-5)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
calcium signaling, reactive oxygen species, second messengers, cell death, cell signaling networks, redox signaling, intracellular calcium stores
MeSH terms
Animals, Calcium, Cell Membrane, Endoplasmic Reticulum, Eukaryotic Cells, Gene Expression Regulation, Humans, Mitochondria, Calcium Channels, Cell Death, Reactive Oxygen Species, Oxidative Stress, NADPH Oxidases, Calcium Signaling, Plasma Membrane Calcium-Transporting ATPases

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