Projektbeschreibung
Molekulare Details zur mitochondrialen Biogenese in Neuronen
Mitochondrien sind die Kraftwerke der Zellen und für den Großteil der Energieversorgung und Bereitstellung von Metaboliten zuständig. Störungen der Mitochondrienfunktion können neurodegenerative und neuropsychiatrische Erkrankungen auslösen. Schwerpunkt des vom Europäischen Forschungsrat finanzierten Projekts MitoPIP ist die Erforschung der mitochondrialen Biogenese in Neuronen, insbesondere die Rolle von Lipiden und deren möglichen negativen Einfluss auf die mitochondriale Lokalisierung in Neuronen, die für die Aufrechterhaltung funktioneller Verbindungen entscheidend ist. So wird getestet, ob sich Mitochondrienstörungen durch spezifische Medikamente zur Lipidmodulation in Neuronen beheben lassen, um letztendlich neurodegenerative und neuropsychiatrische Erkrankungen zu behandeln.
Ziel
Mitochondrial dysfunction leads to several neurodegenerative diseases and is implicated in neuropsychiatric disorders, yet our understanding of how mitochondrial biogenesis is tailored to neurons is very limited. My identification of a role for the phosphatidylinositol-(4,5)bisphosphate (PIP2) phosphatase SYNJ2 in local mitochondrial biogenesis connects phospholipid signalling with mitochondrial maintenance and mitophagy in axons. My lab is already utilizing advanced imaging methods to study RNA transport and local mitochondrial biogenesis. Recent advances in local lipid perturbations now make it possible to also identify lipid-mediated regulatory mechanisms of mitochondrial biogenesis.
This project spans all the way from mitochondrial biochemistry and signaling mechanisms to neuronal cell biology and local translation, culminating in how the molecular effects alter mouse physiology and behavior. We have preliminary evidence that PIP lipids are involved in the regulation of RNA tethering and local translation. This occurs at mitochondria-endosome contacts, which are enriched in PIP lipids. Likewise, contact sites between mitochondria and late-Golgi or lysosomes provide PIP lipids during mitochondrial fission, yet both organelles are rare in axons. SYNJ2a, which is a neuron-enriched splice variant, could underlie the special morphology of axonal mitochondria and contribute to axonal mitochondrial fission. Finally, PIP altering drugs are used for the treatment of mood disorders, and mitochondria and mitophagy have come recently into the spotlight for their role in neuropsychiatric disorders. Alteration of local mitochondrial biogenesis via altered PIP levels may provide a mechanistic link between mitochondria and mood disorders. MitoPIP will be of significance to patients with neurodegenerative and neuropsychiatric diseases, as it will advance our understanding of whether restoration of mitochondrial function in axons can be achieved through regulation of lipids.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
ERC - Support for frontier research (ERC)Gastgebende Einrichtung
80539 Munchen
Deutschland