Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing

•A mutation at the dimer interface of HSD10 has resulted in decreased protein levels in the presence of increased mRNA message.•A mutation in HSD10 causing reduced HSD10 protein results in deficient RNase P activity.•Deficient RNase P activity results in impaired mtDNA transcript processing with elevated amounts of unprocessed RNAs, which are necessary for mitochondrial translation.•Lack of upregulation of mitochondrial enzymes is associated with the most severe mitochondrial biochemical defect and fatal symptoms.•HS10 disease is the third recognized disorder of mitochondrial RNA processing.

Muscle, heart and liver were analyzed in a male subject who succumbed to HSD10 disease. Respiratory chain enzyme analysis and BN-PAGE showed reduced activities and assembly of complexes I, III, IV, and V. The mRNAs of all RNase P subunits were preserved in heart and overexpressed in muscle, but MRPP2 protein was severely decreased. RNase P upregulation correlated with increased expression of mitochondrial biogenesis factors and preserved mitochondrial enzymes in muscle, but not in heart where this compensatory mechanism was incomplete. We demonstrate elevated amounts of unprocessed pre-tRNAs and mRNA transcripts encoding mitochondrial subunits indicating deficient RNase P activity. This study provides evidence of abnormal mitochondrial RNA processing causing mitochondrial energy failure in HSD10 disease.