FASTKD2 is an RNA-binding protein essential for mitochondrial function and oxidative phosphorylation (OXPHOS). Its primary function is assembling the mitochondrial large ribosomal subunit as part of a protein-RNA regulatory module containing RCC1L, NGRN, RPUSD3, RPUSD4, and TRUB2 1. This module controls 16S mitochondrial rRNA abundance and is required for intra-mitochondrial translation 2. FASTKD2 was identified in a genome-wide CRISPR screen as one of 191 genes essential for OXPHOS 2. Biallelic pathogenic variants in FASTKD2 cause Combined Oxidative Phosphorylation Deficiency 44 (COXPD44; MIM# 618855) 3. Disease presentations are clinically heterogeneous, ranging from developmental delay and seizure disorders to acute encephalomyopathy with multi-OXPHOS complex deficiency 4. Notably, hypomorphic variants can produce milder phenotypes, including Lennox-Gastaut syndrome 56. FASTKD2 mutations impair mitochondrial function with particular effects on complexes I, III, and IV, while complex II remains unaffected 4. Beyond mitochondrial disease, FASTKD2 associates with memory performance and hippocampal structure in older adults, suggesting neuroprotective roles 7. The protein also participates in cancer-related pathways and apoptosis regulation 89, though its non-mitochondrial functions require further characterization.