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Mitochondria-Associated Membranes (MAMs) as Hotspot Ca2+ Signaling Units

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Calcium Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 740))

Abstract

The tight interplay between endoplasmic reticulum (ER) and mitochondria is a key determinant of cell function and survival through the control of intracellular calcium (Ca2+) signaling. The specific sites of physical association between ER and mitochondria are known as mitochondria-associated membranes (MAMs). It has recently become clear that MAMs are crucial for highly efficient transmission of Ca2+ from the ER to mitochondria, thus controlling fundamental processes involved in energy production and also determining cell fate by triggering or preventing apoptosis. In this contribution, we summarize the main features of the Ca2+-signaling toolkit, covering also the latest breakthroughs in the field, such as the identification of novel candidate proteins implicated in mitochondrial Ca2+ transport and the recent direct characterization of the high-Ca2+ microdomains between ER and mitochondria. We review the main functions of these two organelles, with special emphasis on Ca2+ handling and on the structural and molecular foundations of the signaling contacts between them. Additionally, we provide important examples of the physiopathological role of this cross-talk, briefly describing the key role played by MAMs proteins in many diseases, and shedding light on the essential role of mitochondria-ER interactions in the maintenance of cellular homeostasis and the determination of cell fate.

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Abbreviations

ΔΨm :

Mitochondrial membrane potential difference

AD:

Alzheimer’s disease

ANT:

Adenine nucleotide translocase

Bap31:

(B-cell receptor-associated protein 31)

BFP:

Blue fluorescent protein

BiP:

Binding immunoglobulin Protein

Ca2+ :

Calcium ions

[Ca2+]:

Ca2+ concentration

[Ca2+]c :

Cytosolic Ca2+ concentration

[Ca2+]m :

Mitochondrial Ca2+ concentration

CABPs:

Intraluminal Ca2+-binding proteins

CaMKII:

Calmodulin-dependent protein kinase II

CCE:

Capacitative Ca2+ entry

Cyp D:

Cyclophilin D

Drp1:

Dynamin-related protein 1

ER:

Endoplasmic reticulum

ERp44:

(Endoplasmic reticulum resident protein 44)

FACL4:

Long-chain fatty acid-CoA ligase type 4

FAD:

Familial Alzheimer’s disease

Fhit:

Fragile histidine triad

Fis1:

Fission 1 homologue

FRET:

Fluorescence resonance energy transfer

GFP:

Green fluorescent protein

GM1:

GM1-ganglioside

grp75:

Glucose-regulated protein 75

HK:

Hexokinase

IMM:

Inner mitochondrial membrane

IMS:

Intermembrane space

IP3:

Inositol 1,4,5-trisphosphate

IP3R:

Inositol 1,4,5-trisphosphate receptor

Letm1:

Leucine zipper-EF-hand containing transmembrane protein 1

MAMs:

Mitochondria-associated membranes

MCU:

Mitochondrial Ca2+ uniporter

MICU1:

Mitochondrial calcium uptake 1

Mfn:

Mitofusin

mHCX:

Mitochondrial H+/Ca2+ exchanger

MMP:

Mitochondrial membrane permeabilization

mNCX:

Mitochondrial Na2+/Ca2+ exchanger

MOMP:

Mitochondrial outer membrane permeabilization

NADH:

Nicotinamide adenine dinucleotide

NCX:

Na2+/Ca2+ exchanger

NE:

nuclear envelope

OMM:

Outer mitochondrial membrane

OPA1:

Optic atrophy 1

OXPHOS:

Oxidative phosphorylation

p66shc:

66-kDa isoform of the growth factor adapter shc

PACS-2:

Phosphofurin acidic cluster sorting protein 2

PAMs:

Plasma membrane associated membranes

PDH:

Pyruvate dehydrogenase

PKA:

Protein kinase A

PKC:

Protein kinase C

PLC:

Phospholipase C

PMCA:

Plasma membrane Ca2+ ATPase

PML:

Promyelocytic leukemia protein

PP2a:

Protein phosphatase 2a

PS1:

Presenilin-1

PS2:

Presenilin-2

PSS-1:

Phosphatidylserine synthase-1

PTP:

Permeability transition pore

ROCs:

Receptor operated Ca2+ channels

ROS:

Reactive oxygen species

RyR:

Ryanodine receptor

SERCA:

Sarco-endoplasmic reticulum Ca2+ ATPase

Sig-1R:

Sigma-1 receptor

SMOCs:

Second messenger operated Ca2+ channels

SR:

Sarcoplasmic reticulum

TIRF:

Total internal reflection fluorescence

TpMs:

Trichoplein/Mitostatin

UCP:

Uncoupling protein

VDAC:

Voltage-dependent anion channel

VOCs:

Voltage operated Ca2+ channels.

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Acknowledgements

A.B. was supported by a research fellowship FISM – Fondazione Italiana Sclerosi Multipla – Cod. 2010/B/1. SP was supported by a training fellowship FISMJ.M.S. was supported by a PhD fellowship from The Foundation for Polish Science (FNP), EU, European Regional Development Fund and Operational Programme “Innovative economy”. This research was supported by: the Polish Ministry of Science and Higher Education under grant NN407 075 137 to M.R.W. and by Telethon (GGP09128), local funds from the University of Ferrara, the Italian Ministry of Education, University and Research (COFIN), the Italian Cystic Fibrosis Research Foundation and Italian Ministry of Health to P.P.

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  1. Laboratory for Technologies of Advanced Therapies (LTTA), Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Via Borsari, 46, 44121, Ferrara, Italy

    Angela Bononi, Sonia Missiroli, Federica Poletti, Jan M. Suski, Chiara Agnoletto, Massimo Bonora, Elena De Marchi, Carlotta Giorgi, Saverio Marchi, Simone Patergnani, Alessandro Rimessi & Paolo Pinton

  2. Nencki Institute of Experimental Biology, Warsaw, Poland

    Jan M. Suski & Mariusz R. Wieckowski

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Bononi, A. et al. (2012). Mitochondria-Associated Membranes (MAMs) as Hotspot Ca2+ Signaling Units. In: Islam, M. (eds) Calcium Signaling. Advances in Experimental Medicine and Biology, vol 740. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2888-2_17

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