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Mitochondria mediated cell death in diabetes

  • Diabetes and Apoptosis
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Abstract

Mitochondrial dysfunction plays a role in the pathogenesis of a wide range of diseases that involve disordered cellular fuel metabolism and survival/death pathways, including neurodegenerative diseases, cancer and diabetes. Cytokine, virus recognition and cellular stress pathways converging on mitochondria cause apoptotic and/or necrotic cell death of β-cells in type-1 diabetes. Moreover, since mitochondria generate crucial metabolic signals for glucose stimulated insulin secretion (GSIS), mitochondrial dysfunction underlies both the functional derangement of GSIS and (over-nutrition) stress-induced apoptotic/necrotic β-cell death, hallmarks of type-2 diabetes. The apparently distinct mechanisms governing β-cell life/death decisions during the development of diabetes provide a remarkable example where remote metabolic, immune and stress signalling meet with mitochondria mediated apoptotic/necrotic death pathways to determine the fate of the β-cell. We summarize the main findings supporting such a pivotal role of mitochondria in β-cell death in the context of current trends in diabetes research.

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Abbreviations

AMPK:

AMP-activated protein kinase

AIF:

Apoptosis inducing factor

ATF3:

Activating transcription factor 3

ATF4:

Activating transcription factor 4

[Ca2+]c :

Cytoplasmic [Ca2+]

[Ca2+]er :

ER luminal [Ca2+]

CHOP:

C/EBP homologous protein

CIC:

Citrate/isocitrate carrier

DAGs:

Diacylglycerols

eIF-2α:

Eukaryotic initiation factor 2 α-subunit

ER:

Endoplasmic reticulum

ERAD:

ER associated degradation

ERRα:

Estrogen related receptor

ETC:

Electron transport chain

GDH:

Glutamate dehydrogenase

GK:

Glucokinase

GSIS:

Glucose stimulated insulin secretion

GSK3:

Glycogen synthase kinase

HK:

Hexokinase

IAPP:

Islet amyloid polypeptide

ICDc:

Cytosolic NADP-dependent isoform of isocitrate dehydrogenase

iNOS:

Inducible nitric oxide synthase

IP3R:

Inositol 1,4,5 trisphosphate receptor

KATP channel:

ATP-sensitive K+ channel

MAM:

Mitochondria associated membrane fraction

MetS:

Metabolic syndrome

Miro:

Mitochondrial Rho GTPase

MPT:

Mitochondrial permeability transition

NF-κB:

Nuclear factor κB

NLRX:

Nucleotide-binding domain and leucine-rich-repeat-containing X protein

NO:

Nitric oxide

NOD:

Non-obese diabetic mouse model

NRF-1 and 2:

Nuclear respiratory factors

OMM:

Outer mitochondrial membrane

OMP:

Outer mitochondrial membrane permeabilization

OXPHOS:

Oxidative phosphorylation

PARP:

Poly(ADP-ribose) polymerase

PC:

Pyruvate carboxylase

PDH:

Pyruvate dehydrogenase

PDK-1:

PDH inhibitor kinase

PERK:

dsRNA-activated protein kinase (PKR)-like ER kinase

PGC-1α:

PPAR-γ co-activator-1α

REDD:

Regulated in development and DNA damage responses

RIG-I:

Retinoic acid inducible gene-I

ROS:

Reactive oxygen species

RyR:

Ryanodine receptor

S1T:

Truncated SERCA1 isoform

SERCAs:

ER/sarcoplasmic reticulum Ca2+ ATPases

STAT-1:

Signal transducer and activator of transcription 1

STING:

Stimulator of interferon genes

T1DM:

Type-1 diabetes

T2DM:

Type-2 diabetes

TGs:

Triglycerides

UPR:

Unfolded protein response

α-KG:

α-Ketoglutarate

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Acknowledgments

G.S. holds grants from the UCL and the Parkinson’s Disease Society. Although we tried to cover all the fundamental results published in the field, we apologise to the authors whose work was not cited due to space restrictions.

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  1. Department of Cell and Developmental Biology, Mitochondrial Biology Group, University College London, Gower Street, WC1E 6BT, London, UK

    Gyorgy Szabadkai & Michael R. Duchen

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  1. Gyorgy Szabadkai
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Correspondence to Gyorgy Szabadkai.

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Szabadkai, G., Duchen, M.R. Mitochondria mediated cell death in diabetes. Apoptosis 14, 1405–1423 (2009). https://doi.org/10.1007/s10495-009-0363-5

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