TransMit
Financiado
Mutations of mtDNA - inheriting without perishing
Mutations of mtDNA cause mitochondrial diseases and are heavily implicated in the pathophysiology of age-associated diseases and ageing. Low levels of mtDNA mutations are universally present in somatic tissues of all humans and mt...
Mutations of mtDNA cause mitochondrial diseases and are heavily implicated in the pathophysiology of age-associated diseases and ageing. Low levels of mtDNA mutations are universally present in somatic tissues of all humans and mtDNA mutations have been reported to contribute to age-associated diseases. Somatic mutations of mtDNA often arise during the massive mtDNA replication in embryogenesis and can accumulate postnatally by clonal expansion. Furthermore, ongoing mtDNA replication during adult life also contributes to the burden of mtDNA mutations in mammalian somatic tissues. Mammalian mtDNA is maternally transmitted without germline recombination and this asexual mode of transmission should theoretically lead to a mutational meltdown over generations, the so-called Muller ratchet. At least two poorly understood mechanisms in the maternal germline counteract the transmission of mutated mtDNA from mother to offspring, i.e., the bottleneck mechanism and purifying selection. The bottleneck mechanism ensures that only a fraction of the pool of mtDNA variation in the mother is transmitted to the offspring. The purifying selection functionally tests mtDNA and decreases transmission of mutations. In this proposal we will use powerful mouse models and completely new experimental strategies to study how mammalian mtDNA mutations are inherited and how somatic mtDNA mutations contribute to age-associated disease and ageing. Maternally inherited pathogenic mtDNA mutations often cause life-threatening incurable diseases with failure of multiple organs in humans. Unfortunately, the principles for inheritance of pathogenic mtDNA mutations are often unclear and the knowledge generated in this proposal will give a better basis for genetic counselling. Furthermore, the mechanisms counteracting a mutational meltdown of the non-recombining, maternally transmitted mtDNA is a central question in biology of great basic scientific interest.
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Duración del proyecto: 64 meses
Fecha Inicio: 2024-05-24
Fecha Fin: 2029-09-30
Fecha Fin: 2029-09-30
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2024-05-24
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2023-ADG:
ERC ADVANCED GRANTS
Cerrada
hace 1 año
Presupuesto
El presupuesto total del proyecto asciende a
3M€
Líder del proyecto
KAROLINSKA INSTITUTET
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5