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Physioxia rewires mitochondrial complex composition to protect stem cell viability

Human induced pluripotent stem cells (hiPSCs) are an invaluable tool to study molecular mechanisms on a human background. Culturing stem cells at an oxygen level different from their microenvironmental niche impacts their viability. To understand this mechanistically, dermal skin fibroblasts of 52 p...

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Main Authors: Raabe, Janice (Author) , Wittig, Ilka (Author) , Laurette, Patrick (Author) , Stathopoulou, Konstantina (Author) , Brand, Theresa (Author) , Schulze, Thomas (Author) , Klampe, Birgit (Author) , Orthey, Ellen (Author) , Cabrera-Orefice, Alfredo (Author) , Meisterknecht, Jana (Author) , Thiemann, Ellen (Author) , Laufer, Sandra D. (Author) , Shibamiya, Aya (Author) , Reinsch, Marina (Author) , Fuchs, Sigrid (Author) , Kaiser, Jennifer (Author) , Yang, Jiaqi (Author) , Zehr, Simonida (Author) , Wrona, Kinga M. (Author) , Lorenz, Kristina (Author) , Lukowski, Robert (Author) , Hansen, Arne (Author) , Gilsbach, Ralf (Author) , Brandes, Ralf P. (Author) , Ulmer, Bärbel M. (Author) , Eschenhagen, Thomas (Author) , Cuello, Friederike (Author)
Format: Article (Journal)
Language:English
Published: November 2024
In: Redox Biology
Year: 2024, Volume: 77, Pages: 1-17
ISSN:2213-2317
DOI:10.1016/j.redox.2024.103352
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.redox.2024.103352
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2213231724003306
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Author Notes:Janice Raabe, Ilka Wittig, Patrick Laurette, Konstantina Stathopoulou, Theresa Brand, Thomas Schulze, Birgit Klampe, Ellen Orthey, Alfredo Cabrera-Orefice, Jana Meisterknecht, Ellen Thiemann, Sandra D. Laufer, Aya Shibamiya, Marina Reinsch, Sigrid Fuchs, Jennifer Kaiser, Jiaqi Yang, Simonida Zehr, Kinga M. Wrona, Kristina Lorenz, Robert Lukowski, Arne Hansen, Ralf Gilsbach, Ralf P. Brandes, Bärbel M. Ulmer, Thomas Eschenhagen, Friederike Cuello

MARC

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520 |a Human induced pluripotent stem cells (hiPSCs) are an invaluable tool to study molecular mechanisms on a human background. Culturing stem cells at an oxygen level different from their microenvironmental niche impacts their viability. To understand this mechanistically, dermal skin fibroblasts of 52 probands were reprogrammed into hiPSCs, followed by either hyperoxic (20 % O2) or physioxic (5 % O2) culture and proteomic profiling. Analysis of chromosomal stability by Giemsa-banding revealed that physioxic -cultured hiPSC clones exhibited less pathological karyotypes than hyperoxic (e.g. 6 % vs. 32 % mosaicism), higher pluripotency as evidenced by higher Stage-Specific Embryonic Antigen 3 positivity, higher glucose consumption and lactate production. Global proteomic analysis demonstrated lower abundance of several subunits of NADH:ubiquinone oxidoreductase (complex I) and an underrepresentation of pathways linked to oxidative phosphorylation and cellular senescence. Accordingly, release of the pro-senescent factor IGFBP3 and β-galactosidase staining were lower in physioxic hiPSCs. RNA- and ATAC-seq profiling revealed a distinct hypoxic transcription factor-binding footprint, amongst others higher expression of the HIF1α-regulated target NDUFA4L2 along with increased chromatin accessibility of the NDUFA4L2 gene locus. While mitochondrial DNA content did not differ between groups, physioxic hiPSCs revealed lower polarized mitochondrial membrane potential, altered mitochondrial network appearance and reduced basal respiration and electron transfer capacity. Blue-native polyacrylamide gel electrophoresis coupled to mass spectrometry of the mitochondrial complexes detected higher abundance of NDUFA4L2 and ATP5IF1 and loss of incorporation into complex IV or V, respectively. Taken together, physioxic culture of hiPSCs improved chromosomal stability, which was associated with downregulation of oxidative phosphorylation and senescence and extensive re-wiring of mitochondrial complex composition. 
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