Descripción del proyecto
Mal plegamiento de las proteínas mitocondriales y restauración de la proteostasis
Muchas enfermedades, incluidos el cáncer y las enfermedades neurodegenerativas, afectan a la función mitocondrial y a la proteostasis, una ruta poco caracterizada en las células de los mamíferos. En el caso de mal plegamiento de las proteínas, las mitocondrias activan la respuesta a proteínas mal plegadas (UPRmt, por sus siglas en inglés) para restaurar la proteostasis. El proyecto mitoUPR, financiado con fondos europeos, aborda la regulación de esta ruta mediante herramientas que inducen la UPRmt en células de mamíferos combinadas con espectrometría de masas cuantitativa, microscopía y secuenciación de próxima generación y edición genética. Además, estudia la influencia que ejerce la UPRmt en los alrededores de la mitocondria, el citosol y las células vecinas. El proyecto aspira a desvelar una nueva capa de regulación del estrés celular asociado con la ruta de UPRmt.
Objetivo
Mitochondrial function is central for cellular metabolism and energy balance. However, many diseases, including cancer and neurodegenerative diseases, affect mitochondrial function and proteostasis. Upon mitochondrial protein misfolding, mitochondria activate the mitochondrial unfolded protein response (UPRmt) to restore proteostasis, a poorly characterized pathway in mammalian cells. Notably, the effects of the UPRmt on its direct environment – mitochondria – and on cytosolic homeostasis remain unknown. Strikingly, non-cell autonomous signaling of metabolism and folding state has been described in recent years, particularly in worms. However, the possible role of UPRmt in such processes is undescribed.
Using newly available tools to acutely induce the UPRmt in mammalian cells, combined with cutting-edge quantitative mass spectrometry, microscopy, next generation sequencing, and gene editing approaches, we propose to address these important open questions by studying the influence UPRmt exerts on the environments of i) mitochondria (including to study the composition and regulation of RNA granules), ii) cytosol (adjustments of translation, metabolism, and proliferation) and iii) neighboring cells (modification by non-cell autonomous signaling). Additionally, we aim to develop an iPSC-based UPRmt model.
On cellular and organismal level, there ought to be mechanisms to signal changes in metabolism and proteostasis to increase robustness in neighboring environments. Studying these effects will be crucial for a better understanding of human disease and carries severe implications: i) the possibility of therapeutic treatment by modulating neighboring compartments or cells and ii) the possibility that diseases inducing the UPRmt could have unknown paracrine and endocrine effects on the organism. This proposal holds the potential to uncover a novel layer of regulation of cellular stress with an extensive influence on our understanding of the UPRmt and disease.
Ámbito científico
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding
- medical and health sciencesclinical medicineoncology
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
- medical and health sciencesbasic medicinephysiologyhomeostasis
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
60323 Frankfurt Am Main
Alemania