Epitranscriptomic regulation of cortical neurogenesis via Mettl8-dependent mitochondrial tRNA m3C modification

Feng Zhang; Kijun Yoon; Daniel Y Zhang; Nam-Shik Kim; Guo-Li Ming; Hongjun Song

doi:10.1016/j.stem.2023.01.007

Epitranscriptomic regulation of cortical neurogenesis via Mettl8-dependent mitochondrial tRNA m³C modification

Cell Stem Cell. 2023 Mar 2;30(3):300-311.e11. doi: 10.1016/j.stem.2023.01.007. Epub 2023 Feb 9.

Authors

Feng Zhang¹, Kijun Yoon¹, Daniel Y Zhang², Nam-Shik Kim¹, Guo-Li Ming³, Hongjun Song⁴

Affiliations

¹ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@pennmedicine.upenn.edu.
⁴ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@pennmedicine.upenn.edu.

Abstract

Increasing evidence implicates the critical roles of various epitranscriptomic RNA modifications in different biological processes. Methyltransferase METTL8 installs 3-methylcytosine (m³C) modification of mitochondrial tRNAs in vitro; however, its role in intact biological systems is unknown. Here, we show that Mettl8 is localized in mitochondria and installs m³C specifically on mitochondrial tRNA^Thr/Ser(UCN) in mouse embryonic cortical neural stem cells. At molecular and cellular levels, Mettl8 deletion in cortical neural stem cells leads to reduced mitochondrial protein translation and attenuated respiration activity. At the functional level, conditional Mettl8 deletion in mice results in impaired embryonic cortical neural stem cell maintenance in vivo, which can be rescued by pharmacologically enhancing mitochondrial functions. Similarly, METTL8 promotes mitochondrial protein expression and neural stem cell maintenance in human forebrain cortical organoids. Together, our study reveals a conserved epitranscriptomic mechanism of Mettl8 and mitochondrial tRNA m³C modification in maintaining embryonic cortical neural stem cells in mice and humans.

Keywords: Mettl8; epitranscriptomics; human forebrain organoids; m(3)C modification; mitochondria activity; mitochondrial tRNA; neural stem cells; neurogenesis.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Humans
Methyltransferases* / genetics
Mice
Mitochondria* / metabolism
Mitochondrial Proteins / metabolism
Neurogenesis
RNA, Transfer / metabolism

Substances

Methyltransferases
RNA, Transfer
Mitochondrial Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding