MTCH2-mediated mitochondrial fusion drives exit from naïve pluripotency in embryonic stem cells
Amir Bahat1*, Andres Goldman1*, Yehudit Zaltsman1, Dilshad H. Khan2, Coral Halperin1, Emmanuel Amzallag1, Vladislav Krupalnik3, Michael Mullokandov1, Alon Silberman1, Ayelet Erez1, Aaron D. Schimmer2, Jacob H. Hanna3, and Atan Gross1# 1Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel 2Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 3Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel
Reprograming of mitochondria metabolism is an established marker during naïve-to-primed pluripotent cell interconversion 1-9 however the role of mitochondria morphology and its molecular regulators remains largely unknown during this critical developmental window. Here we demonstrate using mouse embryonic fibroblasts (MEFs) that mitochondrial MTCH2, a regulator of mitochondrial metabolism10,11, is also a novel regulator of mitochondrial fusion, essential for mitochondrial elongation. In murine embryonic stem cells (ESCs), acute deletion of MTCH2 leads to hyper-fragmentation of mitochondria, which is accompanied by a decrease in mtDNA levels and respiration. In addition, WT cells induced for brief priming elongate mitochondria and metabolically shift from pyruvate oxidation to glutaminolysis, while MTCH2-/- cells preserve fragmented mitochondria morphology, failing to elongate their mitochondria and to shift their mitochondria metabolism. Importantly, MTCH2-/- cells maintain high levels of H3 acetylation and expression of naïve pluripotency markers during the naïve-to-primed interconversion, pointing out their inability to adequately exit naïve pluripotency. Finally, enforced mitochondrial fusion/elongation by the pro-fusion protein Mitofusin (MFN) 2 is sufficient to drive the exit from naïve pluripotency of both MTCH2-/- and wild type ESCs. Taken together, our data indicate that mitochondrial fusion/elongation, governed by MTCH2, mediates metabolic reprogramming and plays a critical role constituting an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.
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