Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

Abstract

Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3′ ends of mitochondrial pre‐tRNAs. Here, we report the identification of 16 novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modeled the residues affected by a missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile‐onset forms of HCM and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism

tRNA Fragments Populations Analysis in Mutants Affecting tRNAs Processing and tRNA Methylation

“…Indeed, mito-RNAse P was shown to recognize, cleave and methylate some mitochondrial tRNAs in vitro, and its activity was enhanced by interaction with a tRNA methylation cofactor (Karasik et al, 2019). Mito-RNAse P and Z dysfunctions have also been linked to several human mitochondrial diseases, as myopathies and neurodevelopmental disorders (Barchiesi and Vascotto, 2019;Saoura et al, 2019). A description of mitochondrial tRFs biogenesis could thus help to better understand the molecular mechanisms underlying these pathologies.…”

Intimate Relations—Mitochondria and Ageing

“…Mitochondrial tRNAs have several structural features that distinguish them from their cytoplasmic counterparts and mitochondria also deviate from the "universal" genetic code (reviewed in [265]. Mutations in mtRNA (or in enzymes related to their post transcriptional modification) are causative of a range of pathologies including myopathy [266,267], hearing loss [268,269] cardiopathy [270,271] and encephalopathy [272,273] and are associated with more than half of all mtDNA-associated human disease [274]. Aberrant post translational modification of mitochondrial tRNAs is also associated with disease.…”

tRNA fragments (tRFs) populations analysis in mutants affecting tRNAs processing and tRNA methylation

“…Indeed, they show that mito-RNAse P recognizes, cleaves and methylates some mitochondrial tRNAs in vitro, which is enhanced by its interaction with a tRNA methylation cofactor (Karasik et al, 2019). Mito-RNAse P and Z dysfunction has been linked to several human mitochondrial diseases, as myopathies and neurodevelopmental disorders (Barchiesi and Vascotto, 2019;Saoura et al, 2019). Describing mitochondrial tRFs biogenesis thus help to better understand the molecular mechanisms linked to these pathologies.…”