Mitochondrial Dysfunction in Huntington’s Disease

  • Catarina Carmo
  • Luana Naia
  • Carla Lopes
  • A. Cristina Rego
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1049)

Abstract

Mitochondrial dysfunction has been described as an early pathological mechanism delineating the selective neurodegeneration that occurs in Huntington’s disease (HD), a polyglutamine-expansion disorder that largely affects the striatum and the cerebral cortex. Over the years, mitochondria roles in eukaryotic cells (e.g. in neurons) have largely diverged from the classically attributed cell power source; indeed, mitochondria not only contribute for synthesis of several metabolites, but are also dynamic organelles that fragment and fuse to achieve a maximal bioenergetic performance, are transported along microtubules, regulate intracellular calcium homeostasis through the interaction with the endoplasmic reticulum, produce free radicals and participate in cell death processes. Indeed, most of these activities have been demonstrated to be affected in HD, potentially contributing for the neuronal dysfunction in pre-symptomatic stages. This chapter resumes some of the evidences that pose mitochondria as a main regulatory organelle in HD-affected neurons, uncovering some potentially therapeutic mitochondrial-based relevant targets.

Keywords

Calcium dyshomeostasis Oxidative stress Metabolic deficits Mitochondrial dynamics Cell death 

Abbreviations

Δψm

Mitochondrial membrane potential

α-KGDH

α-ketoglutarate dehydrogenase

3-NP

3-nitropropionic acid

AIF

Apoptosis inducing factor

Apaf-1

Apoptotic protease-activating factor 1

ATP

Adenosine triphosphate

Bcl-2

B-cell lymphoma 2

BDNF

Brain derived neurotrophic factor

BH3

Bcl-2 homology 3

Bid

BH3 interacting-domain death agonist

Bim

Bcl-2 interacting mediator of cell death

BNIP3

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3

CBP

CREB-binding protein

CK

Creatine kinase

CoQ

Coenzyme Q

CREB

cAMP response element-binding protein

Drp1

Dynamin-related protein 1

ETC

Electron transport chain

Fis1

Mitochondrial fission 1

FMN

Flavin mononucleotide

GABA

γ-aminobutyric acid

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

Gpx

Glutathione peroxidases

GTP

Guanosine triphosphate

H2O2

Hydrogen peroxide

HD

Huntington’s disease

hESC

Human embryonic stem cells

HTT/HTT

Human huntingtin protein/gene

Htt

Rodent huntingtin protein

IAP1

Inhibitor of Apoptosis Protein-1

iPSCs

Induced pluripotent stem cells

K

Lysine

LC3

Light chain 3

MCU

Mitochondrial calcium uniporter

Mff

Mitochondrial fission factor

Mfn

Mitofusin

mHTT

Human mutant HTT

mHtt

Rodent mutant Htt

MIM

Mitochondrial inner membrane

MIS

Mitochondrial intermembrane space

MOM

Mitochondrial outer membrane

mtDNA

Mitochondrial DNA

NAD

β-nicotinamide adenine dinucleotide

ND5

NADH dehydrogenase subunit 5

NRF

Nuclear respiratory factor

Nrf2

Nuclear factor-erythroid 2-related factor-2

OPA1

Optic atrophy 1

OXPHOS

Oxidative phosphorylation

PCr

Phosphocreatine

PDH

Pyruvate dehydrogenase

PGC-1α

PPARγ—coactivator-1α

PINK1

PTEN-induced putative kinase 1

PolyQ

Polyglutamine

PPAR

Peroxisome proliferator-activated receptor

Prx

Peroxiredoxins

PTEN

Phosphatase and tensin homolog

PTP

Permeability transition pore

PUMA

p53 upregulated modulator of apoptosis

ROS

Reactive oxygen species

SDH

Succinate dehydrogenase

Smac/DIABLO

Second mitochondria derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI

SOD

Superoxide dismutase

TAF

TBP-associated factor 4

TBP

TATA-binding protein

TCA

Tricarboxylic acid

Tfam

Mitochondrial transcription factor A

TIM

Translocase of the inner membrane

TRAK

Trafficking kinesin protein

XIAP

X-linked inhibitor of apoptosis

YAC

Yeast artificial chromosome

Notes

Acknowledgements

The authors acknowledge financial support from ‘Fundação para a Ciência e a Tecnologia’ (FCT), Portugal (projects ref. EXPL/BIM-MEC/2220/2013 and Pest-C/SAU/LA0001/2013–2014), co-financed by ‘Programa Operacional Temático Factores de Competividade’ (COMPETE) and supported by the European community fund (FEDER). ACR also acknowledges financial support from ‘Santa Casa da Misericórdia de Lisboa’ (SCML)—Mantero Belard Neuroscience Prize 2013, and ‘Fundação Luso-Americana para o Desenvolvimento’ (FLAD)—Life Science 2020, Portugal. LN holds a Ph.D. fellowship from ‘Fundação para a Ciência e a Tecnologia’ (FCT), Portugal (Reference SFRH/BD/86655/2012). CL was supported by ‘Fundação Luso-Americana para o Desenvolvimento’ (FLAD) Life Science 2020 Postdoctoral Fellowship.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Catarina Carmo
    • 1
  • Luana Naia
    • 1
    • 2
  • Carla Lopes
    • 1
    • 2
  • A. Cristina Rego
    • 1
    • 3
  1. 1.CNC-Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  2. 2.IIIUC-Institute for Interdisciplinary ResearchUniversity of CoimbraCoimbraPortugal
  3. 3.FMUC-Faculty of MedicineUniversity of CoimbraCoimbraPortugal

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