The FASTK family proteins fine-tune mitochondrial RNA processing.

Funder: The Cancer Council of Western AustraliaFunder: UWA Postgraduate ScholarshipsTranscription of the human mitochondrial genome and correct processing of the two long polycistronic transcripts are crucial for oxidative phosphorylation. According to the tRNA punctuation model, nucleolytic processing of these large precursor transcripts occurs mainly through the excision of the tRNAs that flank most rRNAs and mRNAs. However, some mRNAs are not punctuated by tRNAs, and it remains largely unknown how these non-canonical junctions are resolved. The FASTK family proteins are emerging as key players in non-canonical RNA processing. Here, we have generated human cell lines carrying single or combined knockouts of several FASTK family members to investigate their roles in non-canonical RNA processing. The most striking phenotypes were obtained with loss of FASTKD4 and FASTKD5 and with their combined double knockout. Comprehensive mitochondrial transcriptome analyses of these cell lines revealed a defect in processing at several canonical and non-canonical RNA junctions, accompanied by an increase in specific antisense transcripts. Loss of FASTKD5 led to the most severe phenotype with marked defects in mitochondrial translation of key components of the electron transport chain complexes and in oxidative phosphorylation. We reveal that the FASTK protein family members are crucial regulators of non-canonical junction and non-coding mitochondrial RNA processing

Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction

Objective Our goal was to identify the gene(s) associated with an early-onset form of Parkinson disease (PD) and the molecular defects associated with this mutation. Methods We combined whole-exome sequencing and functional genomics to identify the genes associated with early-onset PD. We used fluorescence microscopy, cell, and mitochondrial biology measurements to identify the molecular defects resulting from the identified mutation. Results Here, we report an association of a homozygous variant in CHCHD2, encoding coiled-coil-helix-coiled-coil-helix domain containing protein 2, a mitochondrial protein of unknown function, with an early-onset form of PD in a 26-year-old Caucasian woman. The CHCHD2 mutation in PD patient fibroblasts causes fragmentation of the mitochondrial reticular morphology and results in reduced oxidative phosphorylation at complex I and complex IV. Although patient cells could maintain a proton motive force, reactive oxygen species production was increased, which correlated with an increased metabolic rate. Conclusions Our findings implicate CHCHD2 in the pathogenesis of recessive early-onset PD, expanding the repertoire of mitochondrial proteins that play a direct role in this disease.CC BY-NC-ND 4.0</p