Biology subjects

Bonora, M.

Publications and source records attributed to Bonora, M..

4 recordsLinked to original sources

bioRxiv2026

Decoding EGFR ligand bias through an endocytic organelle platform

How growth factor receptors decode ligand identity into distinct cellular responses remains a fundamental question in cell signaling. Here, we identify a receptor-proximal mechanism that links ligand-specific EGFR activation to distinct endocytic and biological outputs. We show that EGF, but not TGF, selectively engages a RAC1-PLC{gamma}2-IP3R signaling axis that supports EGFR non-clathrin endocytosis (NCE). PLC{gamma}2, but not PLC{gamma}1, localizes to RTN3-dependent PM-ER contact sites, where it generates localized Ca{superscript 2} signals required for completion of NCE, mitochondrial activation and cell motility. This specificity requires the RAC-binding interface of PLC{gamma}2 and is associated with RAC1-dependent formation of CTxB-positive PM regions, indicating that spatial organization contributes to signaling specificity. TGF fails to efficiently assemble the EGFR-associated organelle platform and instead favors clathrin-dependent EGFR uptake, prolonged proliferative signaling, greater organoid yield, and reduced migration compared with EGF. Together, our findings identify the RAC1-PLC{gamma}2 axis as the key determinant that decodes EGFR ligand bias by coupling receptor trafficking to the metabolic program that supports cell migration.

cell biology↗

bioRxiv2024

Dissect mitochondrial activity by transcriptome data with mitology R package

Mitochondria are dynamic organelles that play crucial roles in energy transformation, biosynthesis, and cellular signaling. They actively process biological information, detecting and reacting to both internal and external stimuli. Through intricate physical interactions and diffusion mechanisms within cellular networks, mitochondria integrate diverse inputs and generate signals that finely adjust cellular functions and overall physiology. As a result, the phenotypic expressions of impaired mitochondrial function can exhibit high variability. High-throughput transcriptomic data can capture these changes, but traditional pathway analyses performed on common databases often struggle to specifically detect mitochondrial alterations. This is primarily due to the size of pathways, where the mitochondrial component is typically a small portion of the examined signaling network. To allow a specific exploration of mitochondrial activity through transcriptomic profiles, we developed the mitology R package. We started with a collection of genes whose proteins localize in to the mitochondria, derived from specialized databases like MitoCarta, IMPI, MSeqDR, and from the Gene Ontology database (genes annotated with terms related to mitochondri- in their description). Then, exploiting the mitochondrial gene list, mitology provides ready-to-use implementations of MitoCarta pathways and also a reorganization of general pathway databases, like Reactome and Gene Ontology, with a specific focus on the pathways related to mitochondria activity. Finally, mitology utilizes these mitochondria-focused pathways to conduct mitochondrial pathway analyses, enabling single-sample assessments. Furthermore, we extended the functionality of our package to accommodate classical gene expression data, as well as the newest techniques of single-cell and spatial transcriptomics. Mitology emerges as a novel R package adept at dissecting and unraveling mitochondrial activity, serving as an instrument for conducting targeted mitochondrial studies.

bioinformatics↗

bioRxiv2024

A tripartite organelle platform links growth factor receptor signaling to mitochondrial metabolism

One open question in the biology of growth factor receptors is how a quantitative input (i.e., ligand concentration) is decoded by the cell to produce specific response(s). Here, we show that an EGFR endocytic mechanism, non-clathrin endocytosis (NCE), which is activated only at high ligand concentrations and targets receptor to degradation, requires a tripartite organelle platform involving the plasma membrane (PM), endoplasmic reticulum (ER) and mitochondria. At these contact sites, EGFR-dependent, ER-generated Ca2+ oscillations are sensed by mitochondria, leading to increased metabolism and ATP production. Locally released ATP is required for cortical actin remodeling and EGFR-NCE vesicle fission. The same biochemical circuitry is also needed for an effector function of EGFR, i.e., collective motility. The multiorganelle signaling platform herein described mediates direct communication between EGFR signaling and mitochondrial metabolism, and is predicted to have a broad impact on cell physiology as it is activated by another growth factor receptor, HGFR/MET.

cell biology↗

bioRxiv2020

The P2X7 receptor localizes to the mitochondria, modulates mitochondrial energy metabolism and enhances physical performance

Basal expression of the P2X7 receptor (P2X7R) improves mitochondrial metabolism, ATP synthesis and overall fitness of immune and non-immune cells. We investigated P2X7R contribution to energy metabolism and subcellular localization in fibroblasts (mouse embryo fibroblasts and HEK293 human fibroblasts), mouse microglia (primary brain microglia and the N13 microglia cell line), and heart tissue. The P2X7R localizes to mitochondria, and its lack a) decreases basal respiratory rate, ATP-coupled respiration, maximal uncoupled respiration, resting mitochondrial potential, mitochondrial matrix Ca2+ level, b) modifies expression pattern of oxidative phosphorylation (OxPhos) enzymes, and c) severely affects cardiac performance. Hearts from P2rx7-deleted versus WT mice are larger, heart mitochondria smaller, and stroke volume (SV), ejection fraction (EF), fractional shortening (FS) and cardiac output (CO), are significantly decreased. Accordingly, physical fitness of P2X7R-null mice is severely reduced. Thus, the P2X7R is a key modulator of mitochondrial energy metabolism and a determinant of physical fitness.

cell biology↗