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Journal of Bioenergetics and Biomembranes

, Volume 49, Issue 1, pp 27–47 | Cite as

Mitochondrial Ca2+ and regulation of the permeability transition pore

  • Stephen Hurst
  • Jan Hoek
  • Shey-Shing Sheu
Mini-review

Abstract

The mitochondrial permeability transition pore was originally described in the 1970’s as a Ca2+ activated pore and has since been attributed to the pathogenesis of many diseases. Here we evaluate how each of the current models of the pore complex fit to what is known about how Ca2+ regulates the pore, and any insight that provides into the molecular identity of the pore complex. We also discuss the central role of Ca2+ in modulating the pore’s open probability by directly regulating processes, such as ATP/ADP balance through the tricarboxylic acid cycle, electron transport chain, and mitochondrial membrane potential. We review how Ca2+ influences second messengers such as reactive oxygen/nitrogen species production and polyphosphate formation. We discuss the evidence for how Ca2+ regulates post-translational modification of cyclophilin D including phosphorylation by glycogen synthase kinase 3 beta, deacetylation by sirtuins, and oxidation/ nitrosylation of key residues. Lastly we introduce a novel view into how Ca2+ activated proteolysis through calpains in the mitochondria may be a driver of sustained pore opening during pathologies such as ischemia reperfusion injury.

Keywords

Mitochondrial permeability transition pore Calcium Reactive oxygen species Glycogen synthase kinase 3 Beta Cyclophilin D Calpain 

Abbreviations

2-Oxoglutarate dehydrogenase

(2-ODH)

Aconitase

(ACON)

Adenine nucleotide translocator

(ANT)

Alpha ketoglutarate dehydrogenase

(α-KDH)

Calcium retention capacity

(CRC)

Circularly permuted yellow fluorescence protein

(cpYFP)

Citrate synthase

(CS)

Complex I-V

(CxI-V)

Cyclophilin D

(CypD)

Cyclosporine A

(CsA)

Dynamin-like protein 1

(DLP1)

Electron transport chain

(ETC)

Essential MCU regulator

(EMRE)

Fumarase

(Fum)

Glioblastoma amplified sequence

(GBAS)

Glycogen synthase kinase 3 beta

(GSK-3β)

Hexokinase

(HK)

Inner mitochondrial membrane

(IMM)

Inorganic phosphate

(Pi)

Ischemia reperfusion

(I/R)

Isocitrate dehydrogenase

(IDH)

Leucine Zipper-EF-Hand Containing Transmembrane Protein

(Letm1)

Na+/Ca2+ Li+-permeable exchanger

(NCLX)

Malate dehydrogenase

(MDH)

Mitofusin 2

(MFN2)

Mitochondrial benzodiazepine receptor

(TSPO)

Mitochondrial calcium uniporter

(MCU)

Mitochondrial calcium uniporter regulator 1

(MCUR)1

Mitochondrial calcium uptake

(MICU)

Mitochondrial creatine kinase

(mtCK)

Mitochondrial permeability transition pore

(mPTP)

Mitochondria membrane potential

(ΔΨm)

Mitochondrial ryanodine receptor Type 1

(mRYR1)

N-ethylmaleimide

(NEM)

Nitric oxide synthase

(NOS)

Oligomycin sensitivity conferring protein

(OSCP)

Outer mitochondria membrane

(OMM)

Phenylarsine oxide

(PhAsO)

Phosphate carrier

(PiC)

Polyphosphate

(PolyP)

Pyruvate dehydrogenase

(PDH)

Rapid mode of uptake

(RaM)

Reactive nitrogen species

(RNS)

Reactive oxygen species

(ROS)

S-nitrosylation

(SNO)

S-nitrosoglutathione

(GSNO)

Sarco/endoplasmic reticulum Ca2+-ATPase

(SERCA)

Sirtuin 3

(SIRT3)

Spastic paraplegia 7

(SPG7)

Superoxide dismutase 2

(SOD2)

Tricarboxylic acid

(TCA)

Voltage dependent anion channel

(VDAC)

Notes

Acknowledgments

We would like to acknowledge Jennifer Wilson, for her constructive comments as well as our funding from the National Instute of Health: 2R01HL093671, 1R01HL122124, & 1RO1114760 to S-S. Sheu; T32AA007463 to J. Hoek & S. Hurst, and R01AA018873 to J.Hoek.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Mitocare Center for Mitochondria Research, Department of Pathology Anatomy and Cell BiologyThomas Jefferson UniversityPhiladelphiaUSA

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