Biology subjects

Lisci, M.

Publications and source records attributed to Lisci, M..

3 recordsLinked to original sources

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

FBXW7 alleviates c-MYC repression of pyruvate carboxylase to support metabolic flexibility

Metabolic flexibility, or the ability to adapt to environmental fluctuations, is key to the survival and growth of all living organisms. In mammals, the pathways supporting cell proliferation in nutrient-limiting conditions have not been fully elucidated, although cancers are known to display metabolic dependencies that can be targeted for therapy. Here, we combine systematic nutrient and genome-wide CRISPR/Cas9 screening to provide a comprehensive map of the signaling and metabolic pathways that support cell proliferation in glutamine-limited conditions. We focus on pyruvate anaplerosis and discover a mechanism by which the tumor suppressor FBXW7 controls a MYC-dependent cluster of epigenetic repressors that bind the pyruvate carboxylase (PC) promoter, leading to histone deacetylation, reduced PC expression and glutamine addiction. Our work sheds light on the molecular mechanisms that support metabolic flexibility, and on the nutrients and pathways involved in glutamine dependency, a hallmark of several cancers. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/619388v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@745bc4org.highwire.dtl.DTLVardef@134b07aorg.highwire.dtl.DTLVardef@2e4f8corg.highwire.dtl.DTLVardef@687172_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular 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↗