An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière’s disease
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
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 Ménière’s 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 Ménière’s 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.
Bullet points
-
Genome-wide CRISPR-Cas9 growth screening complements death screening
-
481 genes essential for OXPHOS, including 157 mitochondrial disease genes
-
FAM136A supports mitochondrial intermembrane space protein homeostasis
-
Depletion of FAM136A in Ménière’s disease models causes OXPHOS defects
