Stem Cell Reports
Volume 15, Issue 6, 8 December 2020, Pages 1362-1376
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Article
Insulin Promotes Mitochondrial Respiration and Survival through PI3K/AKT/GSK3 Pathway in Human Embryonic Stem Cells

https://doi.org/10.1016/j.stemcr.2020.10.008Get rights and content
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Highlights

  • Insulin is continuously required to sustain mitochondrial respiration in hESCs

  • Insulin-dependent mitochondrial respiration is substrate specific

  • GSK3 is a major regulator of insulin-dependent respiration and cell survival

  • Insulin is essential for accurate assessment of mitochondrial respiration in hESCs

Summary

Insulin is an essential growth factor for the survival and self-renewal of human embryonic stem cells (hESCs). Although it is best known as the principal hormone promoting glycolysis in somatic cells, insulin's roles in hESC energy metabolism remain unclear. In this report, we demonstrate that insulin is essential to sustain hESC mitochondrial respiration that is rapidly decreased upon insulin removal. Insulin-dependent mitochondrial respiration is stem cell specific, and mainly relies on pyruvate and glutamine, while glucose suppresses excessive oxidative phosphorylation. Pharmacologic and genetic manipulations reveal that continuous insulin signal sustains mitochondrial respiration through PI3K/AKT activation and downstream GSK3 inhibition. We further show that insulin acts through GSK3 inhibition to suppress caspase activation and rescue cell survival. This study uncovers a critical role of the AKT/GSK3 pathway in the regulation of mitochondrial respiration and cell survival, highlighting insulin as an essential factor for accurate assessment of mitochondrial respiration in hESCs.

Keywords

insulin
AKT
GSK3
mitochondrial respiration
caspase
cell survival
human embryonic stem cells

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