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

Deborah Mesa, Elisa Barbieri, Andrea Raimondi, Stefano Freddi, Giorgia Miloro, Gorana Jendrisek, Giusi Caldieri, Micaela Quarto, Irene Schiano Lomoriello, Maria Grazia Malabarba, Arianna Bresci, Francesco Manetti, Federico Vernuccio, Hind Abdo, Giorgio Scita, Letizia Lanzetti, Dario Polli, Carlo Tacchetti, Paolo Pinton, Massimo Bonora, Pier Paolo Di Fiore () and Sara Sigismund ()
Additional contact information
Deborah Mesa: Università degli Studi di Milano
Elisa Barbieri: European Institute of Oncology IRCCS
Andrea Raimondi: IRCCS San Raffaele Hospital Scientific Institute
Stefano Freddi: Università degli Studi di Milano
Giorgia Miloro: European Institute of Oncology IRCCS
Gorana Jendrisek: Università degli Studi di Milano
Giusi Caldieri: European Institute of Oncology IRCCS
Micaela Quarto: Università degli Studi di Milano
Irene Schiano Lomoriello: Università degli Studi di Milano
Maria Grazia Malabarba: Università degli Studi di Milano
Arianna Bresci: Politecnico di Milano
Francesco Manetti: Politecnico di Milano
Federico Vernuccio: Politecnico di Milano
Hind Abdo: The AIRC Institute of Molecular Oncology
Giorgio Scita: Università degli Studi di Milano
Letizia Lanzetti: University of Torino Medical School
Dario Polli: Politecnico di Milano
Carlo Tacchetti: IRCCS San Raffaele Hospital Scientific Institute
Paolo Pinton: University of Ferrara
Massimo Bonora: University of Ferrara
Pier Paolo Di Fiore: Università degli Studi di Milano
Sara Sigismund: Università degli Studi di Milano

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49543-z

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