Apoptosis

, Volume 14, Issue 12, pp 1405–1423

Mitochondria mediated cell death in diabetes

Diabetes and Apoptosis

DOI: 10.1007/s10495-009-0363-5

Cite this article as:
Szabadkai, G. & Duchen, M.R. Apoptosis (2009) 14: 1405. doi:10.1007/s10495-009-0363-5

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 signallingmeet 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.

Keywords

Mitochondria Apoptosis Necrosis β-Cell Diabetes Endoplasmic reticulum stress Virus recognition Cytokine signalling Metabolic overload Metabolic stress 

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

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Cell and Developmental Biology, Mitochondrial Biology GroupUniversity College LondonLondonUK

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