Recazens, E. | Search bioRxiv

bioRxiv2025

An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Meniere disease

Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism and primarily arise from defects in oxidative phosphorylation (OXPHOS). Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging and, to date, most lack a cure. Here, we build on previous efforts to discover genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 "growth" screen, presenting an updated inventory now with 481 OXPHOS genes, including 157 linked to MDs. We further focus on FAM136A, a gene associated with Menieres disease, and show that it supports inter-membrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in a familial form of Menieres disease (fMD), provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in mitochondrial disorders, with the potential to guide future diagnostics and treatments for MDs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/635272v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@1841a8forg.highwire.dtl.DTLVardef@1ebbaa8org.highwire.dtl.DTLVardef@12b70aeorg.highwire.dtl.DTLVardef@f2da2a_HPS_FORMAT_FIGEXP M_FIG C_FIG Bullet pointsO_LIGenome-wide CRISPR-Cas9 growth screening complements death screening C_LIO_LI481 genes essential for OXPHOS, including 157 mitochondrial disease genes C_LIO_LIFAM136A supports mitochondrial intermembrane space protein homeostasis C_LIO_LIDepletion of FAM136A in Menieres disease models causes OXPHOS defects C_LI

cell biology↗

bioRxiv2024

Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing

Mitochondrial biogenesis relies on both the nuclear and mitochondrial genomes, and imbalance in their expression can lead to inborn error of metabolism, inflammation, and aging. Here, we investigate N6AMT1, a nucleo-cytosolic methyltransferase that exhibits genetic co-dependency with mitochondria. We determine transcriptional and translational profiles of N6AMT1 and report that it is required for the cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3), two subunits of the mitochondrial RNAse P enzyme. In the absence of N6AMT1, or when its catalytic activity is abolished, RNA processing within mitochondria is impaired, leading to the accumulation of unprocessed and double-stranded RNA, thus preventing mitochondrial protein synthesis and oxidative phosphorylation. Our work sheds light on the function of N6AMT1 in protein synthesis and highlights a cytosolic program required for proper mitochondrial biogenesis.

molecular biology↗