Popis: |
Summary: Pluripotent stem cells (PSCs) derive energy predominantly from glycolysis and not the energy-efficient oxidative phosphorylation (OXPHOS). Differentiation is initiated with energy metabolic shift from glycolysis to OXPHOS. We investigated the role of mitochondrial energy metabolism in human PSCs using molecular, biochemical, genetic, and pharmacological approaches. We show that the carcinoma protein OCIAD1 interacts with and regulates mitochondrial complex I activity. Energy metabolic assays on live pluripotent cells showed that OCIAD1-depleted cells have increased OXPHOS and may be poised for differentiation. OCIAD1 maintains human embryonic stem cells, and its depletion by CRISPR/Cas9-mediated knockout leads to rapid and increased differentiation upon induction, whereas OCIAD1 overexpression has the opposite effect. Pharmacological alteration of complex I activity was able to rescue the defects of OCIAD1 modulation. Thus, hPSCs can exist in energy metabolic substates. OCIAD1 provides a target to screen for additional modulators of mitochondrial activity to promote transient multipotent precursor expansion or enhance differentiation. : Using modulation of OCIAD1 levels or mitochondrial complex I activity, Shetty et al. demonstrate that energy metabolic substates determine the propensity of human pluripotent stem cells to differentiate. Identifying novel modulators of OCIAD1 or mitochondrial activity will allow transient multipotent precursor expansion or enhance differentiation, important for regenerative applications. Keywords: ovarian carcinoma immunoreactive antigen domain containing-1 (OCIAD1), oxidative phosphorylation (OXPHOS), early mesodermal progenitors (EMPs), mitochondrial complex activity, human embryonic stem cells (hESCs), energy metabolic sub-states of pluripotency, transient multipotent precursor expansion, idebenone, mitochondrial complex I, mitochondrial morphology in live cells |