SDR5C1: a multifunctional protein in health and disease

SDR5C1 is a multifunctional mitochondrial protein. It is a member of the ubiquitous short-chain dehydrogenase/reductase (SDR) enzyme superfamily and is involved in the degradation of isoleucine and short branched-chain fatty acids. Together with the protein TRMT10C it constitutes a methyltransferase responsible for the modification of mitochondrial transfer RNAs (tRNAs). With yet another protein, PRORP, this methyltransferase complex forms a tRNA processing nuclease called ribonuclease P. Thus besides its role in amino acid and fatty acid metabolism, SDR5C1 is critical for the biosynthesis of functional mitochondrial tRNAs, which are required to make proteins for cellular energy production by mitochondrial respiration. Mutations in the X-chromosomal SDR5C1 gene cause a severe disease involving brain and heart. In affected boys disease onset is typically noted at one year of age. Cognitive and motor functions decline rapidly, patients loose vision, develop epilepsy and brain atrophy. The neurological symptoms are accompanied by a severe progressive cardiomyopathy. The majority of patients die at the age of 24 years. Due to elevated levels of isoleucine- degradation intermediates in the urine of the patients, the disease was originally considered a metabolic disease and designated MHBD (2-methyl-3-hydroxybutyryl-CoA dehydrogenase) deficiency. However, the clinical symptoms and more recent experimental evidence indicate that the disease might actually be due to mitochondrial respiratory dysfunction and not to a deficiency of isoleucine metabolism. The aim of this project is to clarify the pathomechanisms of the disease caused by mutations in the SDR5C1 gene. We propose that an impairment of SDR5C1`s role in mitochondrial tRNA biosynthesis is responsible for mitochondrial respiratory dysfunction and consequently disease. The hypothesis will be tested biochemically and in a novel disease model of genome engineered cells.

SDR5C1 is an amino and fatty acid degrading enzyme, and in addition a component of human mitochondrial ribonuclease P (RNase P), which is an enzyme crucial for transfer RNA (tRNA) biosynthesis. Moreover, a subcomplex of mitochondrial RNase P, also involving SDR5C1, catalyzes a specific chemical modification of mitochondrial tRNAs, which is thought to stabilize their structure. Missense mutations in the gene of SDR5C1 cause a disease characterized by progressive neurodegeneration and cardiomyopathy, called HSD10 disease. In this project we investigated the effect of selected mutations on SDR5C1s functions. We could show that pathogenic mutations impair not only SDR5C1-dependent amino/fatty acid degradation, as already known before, but also tRNA processing and methylation, the latter two providing a better rational as the molecular mechanism underlying the mitochondrial dysfunction observed in HSD10 patients than the previously supposed role of SDR5C1 in amino acid degradation. More specifically we showed that the mutations disrupt the structure of SDR5C1 and/or impair its interaction with other subunits of the mitochondrial RNase P complex, and thereby lead to the mitochondrial dysfunction observed in HSD10 patients. Furthermore, the project advanced our conceptional understanding of the molecular mechanisms of the mitochondrial RNase P multi-enzyme complex, of how and why three different proteins with distinct enzymatic activities have to operate together to achieve their tRNA-related catalytic functions.