Biology subjects

Suleyman, O.

Publications and source records attributed to Suleyman, O..

4 recordsLinked to original sources

bioRxiv2025

Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development

To grow and divide cells must tightly coordinate anabolic programs with the availability of nutrients and growth factors. This balance is especially critical during postnatal development, when biosynthetic and energetic demands are high, and nutrient supply and neonates have to adapt to periods of fasting. These conditions place acute stress on the proteostasis network, making autophagy essential for nutrient recycling. We found that the chaperone aryl hydrocarbon receptor-interacting protein (AIP) supports both arms of this metabolic balance: promoting anabolic PI3K-AKT signaling for mTORC1 activation and enabling catabolic processes such as proteasomal degradation and autophagy. Loss of AIP causes a severe neonatal metabolic disorder, where affected infants fail to thrive postnatally. Our findings establish AIP as a central regulator of neonatal metabolic adaptation and cellular homeostasis. One Sentence SummaryAIP integrates nutrient sensing and protein recycling to sustain neonatal survival.

developmental biology↗

bioRxiv2024

A cleaved cytosolic FOXG1 promotes excitatory neurogenesis by modulation of mitochondrial translation - a new therapeutic target for brain disorders.

The modulation of mitochondrial function is core to cell fate decisions and tissue homeostasis, yet the mechanisms regulating these processes remain poorly understood. Here, we demonstrate that mitochondrial OXPHOS activity is controlled in a tissue-specific manner through a non-canonical cytoplasmic function of the transcription factor FOXG1. A temporally regulated short cytoplasmic FOXG1 interacts with mitochondrial ribosomal proteins and enhances translation of mt-DNA-encoded OXPHOS proteins. Zebrafish and human models of early nonsense FOXG1 syndrome mutations unexpectedly produce a short C-terminal peptide. Expression of this truncated protein drives an overproduction of excitatory neurons and induces a structural, functional, and translational phenotype in mutant mitochondria. We demonstrate that this activity is a gain of function, normally carried out by a cleaved FOXG1 in wildtype. Both normal and mutant peptides are transported to the mitochondria, interact with mito-ribosomal proteins to enhance translation, thereby stimulating neurogenesis. Adjusting the dosage of the mutant peptide rescues the excitatory aspect of the FOXG1 syndrome. Our study demonstrates a novel role for cytoplasmic Foxg1 in promoting neurogenesis via the tuning of mitochondrial translation and provides the first evidence for direct tissue-specific control of OXPHOS activity. This study opens a novel therapeutic avenue for the treatment of disorders associated with mitochondrial hypoactivity. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/607559v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b8806forg.highwire.dtl.DTLVardef@1f81e3forg.highwire.dtl.DTLVardef@89d9e1org.highwire.dtl.DTLVardef@3f7a72_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Biallelic Loss of Molecular Chaperone Molecule AIP Results in a Novel Severe Multisystem Disease Defined by Defective Proteostasis

Children born with deleterious biallelic variants of the chaperone aryl hydrocarbon receptor interacting protein (AIP) have a novel pediatric metabolic disease presenting a severe, complex clinical phenotype characterized by failure to develop following birth. Analysis of Aip knockout mouse embryonic fibroblasts and patient-derived dermal fibroblasts revealed that AIP was required to support proteostasis; including proteasome activity, induction of autophagy and lysosome function. aip knockout zebrafish, recapitulated the phenotype of the children; dying at an early stage of development when autophagy is required to adapt to periods of starvation. Our results demonstrate that AIP plays a crucial role in initiating autophagy and maintaining proteostasis in vitro and in vivo. One Sentence SummaryHomozygous loss of the chaperone AIP results in a novel pediatric disease exhibiting multiple features of a lysosomal storage disease.

molecular biology↗

bioRxiv2019

Analysis tools to quantify dissemination of pathology in zebrafish larvae

We used the zebrafish larval Mycobacterium marinum infection model of tuberculosis to develop image analysis software called QuantiFish, to enable rapid, objective quantitation of bacterial load and dissemination. Our analysis tools provide novel outcome measures of infection; the proportional distribution of bacteria between sites and their spatial distribution throughout the host. We anticipate the broader application of these parameters to other zebrafish models of infection and metastatic cancer.

microbiology↗