Descripción del proyecto
El complejo I como diana principal para curar las enfermedades mitocondriales
Las mitocondrias son los centros energéticos de la célula y generan la mayor parte del trifosfato de adenosina (ATP, por sus siglas en inglés) celular a través de una cadena respiratoria acoplada a la fosforilación oxidativa. La oxidación del dinucleótido de adenina y nicotinamida reducido (NADH, por sus siglas en inglés) por la enzima NADH:ubiquinona oxidorreductasa (complejo I) proporciona la principal fuerza motriz para la síntesis de ATP. La deficiencia del complejo I es la patología más común en las enfermedades mitocondriales, el parkinsonismo, la diabetes, el cáncer y el envejecimiento. Los datos preliminares han demostrado que la estabilización del complejo I podría mejorar los síntomas de la deficiencia respiratoria en modelos celulares de disfunción mitocondrial, y esta estabilización podría lograrse con la pérdida de la peptidasa caseinolítica. El objetivo del proyecto CICURE, financiado con fondos europeos, es investigar la posibilidad de actuar de forma selectiva sobre la peptidasa caseinolítica localizada en la matriz mitocondrial para mejorar los síntomas de las enfermedades mitocondriales utilizando modelos genéticos «in vivo».
Objetivo
Mitochondria are found within every human cell and are responsible for the majority of energy production in the cell. When the mitochondria do not function properly, they cause devastating diseases affecting many and often multiple organs with the highest energy needs, such as skeletal muscle, brain, heart and liver. Over the years we have steadily increased our understanding of the genetic and molecular mechanisms leading to mitochondrial disease, developed different models and biomarkers. Unfortunately, development of effective therapeutic approaches able to improve the outcome of the diseases or at least to ameliorate or postpone the symptoms was much less effective.
Today, therapeutic options for mitochondrial diseases still remain focused on supportive dietary interventions aimed at relieving complications. Therefore, it would be ideal if a single approach could be developed that would be equally effective with various mitochondrial diseases most often characterized by complex I deficiency.
Our preliminary data show that by removing the major mitochondrial matrix protease CLPXP, and therefore stabilizing CI, we could ameliorate the symptoms of respiratory deficiency in different cellular models of mitochondrial dysfunction. The loss of CLPP in these models resulted not only in increased stability of CI, but also normalized NAD+/ NADH that collectively resulted in improved proliferation and survival rates. Remarkably, even partial loss of ClpXP activity in respiratory deficient cells led to mild increase in the CI levels, opening an exciting prospect for therapeutic interventions. Therefore, the overall goal of this project is to explore the possibility of targeting CLPP activity to ameliorate symptoms of mitochondrial diseases in in vivo models through genetic interventions and search for specific protease inhibitors.
Palabras clave
Programa(s)
Régimen de financiación
ERC-POC - Proof of Concept GrantInstitución de acogida
50937 Koeln
Alemania