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Revisiting Mitochondrial Function and Metabolism in Pluripotent Stem Cells: Where Do We Stand in Neurological Diseases?

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Abstract

Pluripotent stem cells (PSCs) are powerful cellular tools that can generate all the different cell types of the body, and thus overcome the often limited access to human disease tissues; this becomes highly relevant when aiming to investigate cellular (dys)function in diseases affecting the central nervous system. Recent studies have demonstrated that PSC and differentiated cells show altered mitochondrial function and metabolic profiles and production of reactive oxygen species. This raises an emerging paradigm about the role of mitochondria in stem cell biology and urges the need to identify mitochondrial pathways involved in these processes. In this respect, this review focuses on the metabolic profile of PSC and how mitochondrial function can influence the reprogramming and differentiation processes. Indeed, both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) favor the glycolytic pathway as a major source of energy production over oxidative phosphorylation. PSC mitochondria are characterized by a spherical shape, low copy number of mitochondrial DNA, and a hyperpolarized state. Indeed, mitochondria appear to have a crucial role in reprogramming iPSC, in the maintenance of a pluripotent state, and in differentiation. Moreover, an increase in mitochondrial oxidative phosphorylation has to occur for differentiation to succeed. Therefore, in vitro differentiation of neural stem cells (NSCs) into neurons can be compromised if those mechanisms are impaired. Future research should shed light on how mitochondrial impairment occurring in pre differentiation neural stages (e.g., in NSC or premature neurons) may contribute for the etiopathogenesis of neurodevelopmental and neurological disorders.

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Abbreviations

NSC:

Neural stem cells

PSC:

Pluripotent stem cells

iPSC:

Induced pluripotent stem cells

hESC:

Human embryonic stem cells

EBs:

Embryoid bodies

SSEA:

Stage Specific Embryonic Antigens

Sox2:

High-mobility-group (HMG)-box protein-2

Klf4:

Kruppel-like factor-4

cDNAs:

Complementary DNAs

ROS:

Reactive oxygen species

PPP:

Pentose phosphate pathway

NADPH:

Nicotinamide adenine dinucleotide phosphate reduced

GSH:

Reduced glutathione

acetyl-CoA:

Acetyl-coenzyme A

PDH:

Pyruvate dehydrogenase

OXPHOS:

Oxidative phosphorylation

mtDNA:

Mitochondrial DNA

ΔΨm :

Mitochondrial membrane potential

MEFs:

Mouse embryonic fibroblasts

LDH:

Lactate dehydrogenase

HIF1α:

Hypoxia-inducible factor one alpha

PDK3:

PDH kinase 3

PKM2:

Pyruvate kinase M2 isoform

TCA:

Tricarboxylic acid

GSK3:

Glycogen synthase kinase-3

MEK/MAPK:

Mitogen-activated protein kinase

OCR:

Oxygen consumption rate

FCCP:

Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone

mESC:

Mouse ESC

COX:

Cyclooxygenase

LOX:

Lipoxygenase

PTK:

Palmityl trifluoromethyl ketone

SAM:

S-adenosyl methionine

Thr:

Threonine

Tdh:

Threonine dehydrogenase

H3K4me3:

Histone H3 lysine 4

UCP:

Uncoupling proteins

SOD:

Superoxide dismutase

GPX:

Glutathione peroxidase

Nox:

NADPH oxidase

Drp1:

Dynamin-related protein

Fis1:

Mitochondrial fission 1

Mfn:

Mitofusin

Opa1:

Optic atrophy type 1

Gfer:

Growth factor erv1-like

TFAM:

Mitochondrial transcription factor A

PGC-1α:

Peroxisome proliferator-activated receptor-c coactivator-1α

POLG:

DNA polymerase γ

NRF-1:

Nuclear respiratory factor-1

mTOR:

Mammalian target of rapamycin

YY1:

Transcription factor yang 1

AD:

Alzheimer Disease

PD:

Parkinson Disease

HD:

Huntington Disease

NPCs:

Neural progenitor cells

FRDA:

Friedreich ataxia

FXN :

Frataxin gene

LRRK2:

Leucine-rich repeat kinase-2

PINK:

PTEN-induced putative kinase

DARPP-32:

Dopamine- and cAMP-regulated neuronal phosphoprotein

BDNF:

Brain-derived neurotrophic factor

3-MA:

3-methyladenine

GST:

Glutathione S-transferase

Prx:

Peroxiredoxin

FAD:

Familial form of AD

PS:

Presenilin

APP:

Amyloid precursor protein.

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Acknowledgments

AC Rego research is funded by FEDER funds through the Operational Programme Competitiveness Factors—COMPETE and national funds by ‘Fundação para a Ciência e a Tecnologia’ (FCT) from CNC.IBILI strategic project PEst-C/SAU/LA0001/2013-2014 and UID/NEU/04539/2013, and ‘Fundação Luso-Americana para o Desenvolvimento’ (FLAD) Life Science 2020, Portugal. C Lopes was a recipient of a PhD fellowship from FCT, Portugal, reference SFRH/BD/51192/2010.

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  1. Doctoral Programme in Experimental Biology and Biomedicine of the CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Carla Lopes

  2. Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal

    Carla Lopes

  3. Center for Neuroscience and Cell Biology, and Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal

    A. Cristina Rego

  4. Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    A. Cristina Rego

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  1. Carla Lopes
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Lopes, C., Rego, A.C. Revisiting Mitochondrial Function and Metabolism in Pluripotent Stem Cells: Where Do We Stand in Neurological Diseases?. Mol Neurobiol 54, 1858–1873 (2017). https://doi.org/10.1007/s12035-016-9714-8

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