Mitochondria-lysosome crosstalk as a driver of age-related pathology

Objetivo temático: Lysosomes play an essential role in mitochondrial homeostasis and inflammation via sensing of mitochondrial contents, and that the persistent activation of this pathway results in chronic inflammation.

Área Científica: Bioquímica, Biologia Celular, Neurociências ou áreas afins

Síntese do Projeto: Mitochondria and lysosomes are fundamental signalling platforms that regulate key aspects of cell function. The lifecycle of mitochondria ends with lysosomal degradation. We observed that a common consequence of lysosomal malfunction is the accumulation of undigested mitochondrial contents in the lysosome, which triggers repression of mitochondrial biogenesis and activates lysosomal Toll-like receptor signalling (TLR) and downstream inflammation cascades. We thus hypothesize that lysosomes play an essential role in mitochondrial homeostasis and inflammation via sensing of mitochondrial contents, and that the persistent activation of this pathway results in chronic inflammation.

To test this hypothesis, we will first determine the mechanisms by which lysosomal sensing of mitochondrial contents regulates the transcriptional program of mitochondrial biogenesis, and how different pathways of delivering mitochondrial contents to lysosomes affect this process. Secondly, we will test how undigested mitochondrial contents remaining for extended periods in dysfunctional lysosomes activate TLR signalling and inflammation and test in vivo in a mouse model of age-related neurodegeneration if thisamplification loop is a driving force of aging brain pathology. Third, we will test the hypothesis that inflammation triggered by damaged mitochondria/lysosomes increases metabolic reliance on these organelles, thus creating an inflammatory amplification loop,

Overall, this project tackles the nascent concept of mitochondria-lysosome crosstalk. Furthermore, by testing if inflammation triggered by mitochondria-lysosome crosstalk drives the onset of neurodegenerative disease, we seek to define a novel and presymptomatic therapeutic target. The mitolysoAGING project addresses key timely questions of molecular medicine, cell biology and metabolism. Our expertise in mitochondria-lysosome signalling, track record and multi-disciplinary environment set the right context for this project.

Investigador Responsável na UC: Nuno Raimundo

Unidade Orgânica UC: MIA Portugal

Instituições participantes no Projeto: Universidade de Coimbra

Instituição Financiadora/Gestora: Fundação para a Ciência e Tecnologia (FCT)

Programa de Financiamento: Programa ERC Portugal

Período de execução: 01/09/2023 a 31/08/2026 (36 meses)

Custo total elegível (EUR): 250.000€

Apoio financeiro da UE: n.a

Apoio financeiro público nacional: 250.000€

Técnico do Projeto: Filipa Delgadinho _ filipa.delgadinho@uc.pt

Contacto: + 351 239 247 015 _ (Ext. 210027)