FASTKD5 is a mitochondrial endonuclease essential for processing non-canonical mitochondrial mRNA precursors 1. It catalyzes endonucleolytic cleavage of primary polycistronic mitochondrial transcripts at three non-canonical sites (CO1, CO3, and CYB mRNAs) that lack flanking transfer RNAs 2. FASTKD5 recognizes specific RNA structural features 13-15 nucleotides upstream of cleavage sites through substrate-specific amino acid residues, with a critical active site residue required for processing all three substrates 2. This processing is vital for translating cytochrome c oxidase subunits and assembling respiratory complex IV 3. FASTKD5 serves as a critical regulatory control point coordinating nuclear and mitochondrial gene expression to achieve balanced oxidative phosphorylation biogenesis 45. During HIV-1 infection, FASTKD5 associates with the innate immune receptor NLRX1 to enhance mitochondrial respiratory complex expression 6. Loss of FASTKD5 produces severe oxidative phosphorylation assembly defects and impaired electron transport chain translation 7. Bi-allelic FASTKD5 mutations cause cytochrome c oxidase deficiency and Leigh syndrome, a progressive neurodegenerative disease, with severity correlating to pathogenic variant type 3. FASTKD5 alterations occur in multiple cancer types, suggesting therapeutic potential 8.