Merm1: a novel regulator of mitochondrial transcription and function

Abstract

Metastasis-related methyltransferase 1 (Merm1) is a highly conserved protein which mediates N7-methylation of G1639 on ribosomal 18S RNA (1). Here, we identify a novel role for Merm1 in modulating mitochondrial transcription and thereby function. Merm1 function was investigated by siRNA mediated knockdown followed by RNAseq analysis, revealing reduced abundance of all mitochondrially encoded transcripts. This observation was corroborated by qPCR analysis, and there was no change in mitochondrial genome copy number. The changes in mitochondrial transcript abundance induced by Merm1 knockdown were found to be functionally important, reducing basal mitochondrial respiration, spare respiratory capacity and ATP production, as measured by Seahorse™ XF analyser. Immunofluorescence imaging combined with subcellular fractionation studies in A549 cells did not co-localise Merm1 within mitochondria. We therefore propose that Merm1 is eliciting these effects from outside the mitochondria, through its role as a ribosomal modulator. Importantly, in a panel of ~400 exomes from patients with unexplained mitochondrial defects, three heterozygous exonic missense mutations were identified in the Merm1 gene. Delineating the mechanism by which Merm1 regulates mitochondrial function may inform new therapies with clinical impact.