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CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.

Alison Galloway,Kasia Knop,C. Gómez-Moreira,Vanessa Xavier,Sarah Thomson,Harunori Yoshikawa,Olga Suska,Radoslaw Lukoszek,Aneesa Kaskar,A. Lamond,Thomas MacVicar,V. Cowling

Published 2025 in Cell Reports

ABSTRACT

During T cell activation, mitochondrial biogenesis and cellular metabolism are altered to meet the elevated energy demands of protein synthesis, rapid proliferation, and effector T cell function. The mechanisms coupling mitochondrial dynamics to T cell status are unclear. Here, we report that RNA cap methyltransferase 1 (CMTR1) is induced in activated T cells, methylating the first nucleotide on mRNA and U2 small nuclear RNA (snRNA), a component of the spliceosome. Using transcriptomic analyses, we identify a functional splicing module regulating mitochondrial dynamics in T cells, which alters the isoforms of proteins controlling mitochondrial fission and fusion. Through epitranscriptomic control of U2 snRNA and splicing, CMTR1 directs protein isoform selection during T cell activation to promote the development of longer mitochondria with increased respiratory capacity. Thus, CMTR1 upregulation supports the energetic demands of T cell activation, survival, and immune responses.

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