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.
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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:
-
p 53 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
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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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Carmo, C., Naia, L., Lopes, C., Rego, A.C. (2018). Mitochondrial Dysfunction in Huntington’s Disease. In: Nóbrega, C., Pereira de Almeida, L. (eds) Polyglutamine Disorders. Advances in Experimental Medicine and Biology, vol 1049. Springer, Cham. https://doi.org/10.1007/978-3-319-71779-1_3
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