Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells.
The relationship between mitochondrial metabolism and cell viability and differentiation in stem cells (SCs) remains poorly understood. In the present study, we compared mitochondrial physiology and metabolism between P19SCs before/after differentiation and present a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts, pluripotency of P19SCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity: round, low-polarized and inactive mitochondria with a closed permeability transition pore. This decreased mitochondrial capacity increased their resistance against dichloroacetate. Thus, stimulation of mitochondrial function by growing P19SCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19SCs sensitive to dichloroacetate. Because of the central role of this type of SCs in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In addition, the present work suggests the regulation of mitochondrial metabolism as a tool for inducing cell differentiation in stem line therapies.
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
I
I
Vega-Naredo
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
R
R
Loureiro
1] CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal [2] Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
K A
KA
Mesquita
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
I A
IA
Barbosa
1] CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal [2] Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
L C
LC
Tavares
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
A F
AF
Branco
Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
J R
JR
Erickson
Department of Biomedical Sciences, University of Minnesota-Duluth, Duluth, MN 55812, USA.
J
J
Holy
Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
E L
EL
Perkins
1] CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal [2] Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
R A
RA
Carvalho
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Lot 8A, Biocant Park, 3060-197 Cantanhede, Portugal.
P J
PJ
Oliveira
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D056915:DNA Copy Number Variations / Q000235:genetics; D003999:Dichloroacetic Acid / Q000494:pharmacology; D054278:Embryonal Carcinoma Stem Cells / Q000166:cytology*; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010101:Oxygen Consumption; D039904:Pluripotent Stem Cells / Q000166:cytology*; D018874:Spheroids, Cellular; D018243:Teratocarcinoma / Q000196:embryology; D014407:Tumor Cells, Cultured
D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid; D005947:Glucose