MTCH2-mediated mitochondrial fusion drives exit from naïve pluripotency in embryonic stem cells

Nat Commun. 2018 Dec 3;9(1):5132. doi: 10.1038/s41467-018-07519-w.

Abstract

The role of mitochondria dynamics and its molecular regulators remains largely unknown during naïve-to-primed pluripotent cell interconversion. Here we report that mitochondrial MTCH2 is a regulator of mitochondrial fusion, essential for the naïve-to-primed interconversion of murine embryonic stem cells (ESCs). During this interconversion, wild-type ESCs elongate their mitochondria and slightly alter their glutamine utilization. In contrast, MTCH2-/- ESCs fail to elongate their mitochondria and to alter their metabolism, maintaining high levels of histone acetylation and expression of naïve pluripotency markers. Importantly, enforced mitochondria elongation by the pro-fusion protein Mitofusin (MFN) 2 or by a dominant negative form of the pro-fission protein dynamin-related protein (DRP) 1 is sufficient to drive the exit from naïve pluripotency of both MTCH2-/- and wild-type ESCs. Taken together, our data indicate that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dynamins / genetics
  • Dynamins / metabolism
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Gene Expression
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / genetics*
  • Mitochondrial Membrane Transport Proteins / genetics*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Nanog Homeobox Protein / genetics
  • Nanog Homeobox Protein / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*

Substances

  • Mitochondrial Membrane Transport Proteins
  • Mtch2 protein, mouse
  • Nanog Homeobox Protein
  • GTP Phosphohydrolases
  • Mfn2 protein, mouse
  • Dnm1l protein, mouse
  • Dynamins