FASTK post-transcriptional regulators – a ‘FAST-tracK’ in mitochondrial gene expression

Fas-activated post-transcriptional regulators. Members are classified based on their conserved C-terminus, which shows homology with the PD-(D/E)XK superfamily of endoribonucleases. However, it is still uncertain which of these FASTK members are catalytic. The six human FASTK homologs rely on their RNA-binding activity to regulate distinct stages of mitochondrial gene expression, including early processing of nascent RNA, 3′-end messenger RNA (mRNA) maturation, ribosomal RNA (rRNA) modification, mRNA stability, and translation. Genetic and genomic studies have highlighted the crucial role of FASTK proteins in balancing the mitochondrial transcriptome and controlling oxidative phosphorylation. However, until recently, the molecular mechanisms governing their RNA metabolic activities have remained elusive. New biochemical and structural advances have provided molecular insights into the architecture and regulation of FASTK proteins. Here, we summarize the current understanding of the FASTK family’s specialized roles in gene regulation, with an emphasis on mitochondrial mRNA metabolism by the proteins FASTK, FASTK domain-con-taining protein 4 (FASTKD4), and FASTKD5. Additionally, we leverage recent experimental structures and artificial intelligence-based prediction models to explore the molecular organization of FASTK proteins and highlight the family’s signature C-terminus, a region essential for their RNA-binding activity.