BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells

Redox Biol. 2017 Oct:13:426-443. doi: 10.1016/j.redox.2017.07.004. Epub 2017 Jul 4.

Abstract

Mitophagy under hypoxia is an important factor for maintaining and regulating stem cell functions. We previously demonstrated that fatty acid synthase (FASN) induced by hypoxia is a critical lipid metabolic factor determining the therapeutic efficacy of umbilical cord blood-derived human mesenchymal stem cells (UCB-hMSCs). Therefore, we investigated the mechanism of a major mitophagy regulator controlling lipid metabolism and therapeutic potential of UCB-hMSCs. This study revealed that Bcl2/adenovirus E1B 19kDa protein-interacting protein 3 (BNIP3)-dependent mitophagy is important for reducing mitochondrial reactive oxygen species accumulation, anti-apoptosis, and migration under hypoxia. And, BNIP3 expression was regulated by CREB binding protein-mediated transcriptional actions of HIF-1α and FOXO3. Silencing of BNIP3 suppressed free fatty acid (FFA) synthesis regulated by SREBP1/FASN pathway, which is involved in UCB-hMSC apoptosis via caspases cleavage and migration via cofilin-1-mediated F-actin reorganization in hypoxia. Moreover, reduced mouse skin wound-healing capacity of UCB-hMSC with hypoxia pretreatment by BNIP3 silencing was recovered by palmitic acid. Collectively, our findings suggest that BNIP3-mediated mitophagy under hypoxia leads to FASN-induced FFA synthesis, which is critical for therapeutic potential of UCB-hMSCs with hypoxia pretreatment.

Keywords: Bcl2/adenovirus E1B 19kDa protein-interacting protein 3 (BNIP3); Fatty acid synthase (FASN); Hypoxia; Mesenchymal stem cell; Mitophagy.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Hypoxia
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Fatty Acid Synthase, Type I / metabolism
  • Fatty Acids / metabolism*
  • Forkhead Box Protein O3 / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mitochondria / metabolism
  • Mitophagy
  • Oxygen / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Reactive Oxygen Species / metabolism
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Wound Healing*

Substances

  • BNIP3 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • FOXO3 protein, human
  • Fatty Acids
  • Forkhead Box Protein O3
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • Oxygen