Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex.
SDR5C1 is an amino and fatty acid dehydrogenase/reductase, moonlighting as a component of human mitochondrial RNase P, which is the enzyme removing 5'-extensions of tRNAs, an early and crucial step in tRNA maturation. Moreover, a subcomplex of mitochondrial RNase P catalyzes the N(1)-methylation of purines at position 9, a modification found in most mitochondrial tRNAs and thought to stabilize their structure. Missense mutations in SDR5C1 cause a disease characterized by progressive neurodegeneration and cardiomyopathy, called HSD10 disease. We have investigated the effect of selected mutations on SDR5C1's functions. We show that pathogenic mutations impair SDR5C1-dependent dehydrogenation, tRNA processing and methylation. Some mutations disrupt the homotetramerization of SDR5C1 and/or impair its interaction with TRMT10C, the methyltransferase subunit of the mitochondrial RNase P complex. We propose that the structural and functional alterations of SDR5C1 impair mitochondrial RNA processing and modification, leading to the mitochondrial dysfunction observed in HSD10 patients.
Center for Anatomy & Cell Biology, Medical University of Vienna, 1090 Vienna, Austria.
Elisa
E
Vilardo
Center for Anatomy & Cell Biology, Medical University of Vienna, 1090 Vienna, Austria walter.rossmanith@meduniwien.ac.at.
Walter
W
Rossmanith
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency* / Q000235:genetics; D020820:Dyskinesias; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics*; D038901:X-Linked Intellectual Disability; D008780:Methyltransferases / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D012323:RNA Processing, Post-Transcriptional; D012343:RNA, Transfer / Q000378:metabolism; D043262:Ribonuclease P / Q000378:metabolism*
D012343:RNA, Transfer; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; D008780:Methyltransferases; C578375:TRMT10c protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D043262:Ribonuclease P