Metabolic adaptations in liver-specifi OPA1 knockout model
- Autores: Susana Raquel Costa Barros
- Directores de la Tesis: Antonio Zorzano Olarte (dir. tes.), María Isabel Hernández Alvarez (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2020
- Idioma: inglés
- Tribunal Calificador de la Tesis: Laura Herrero Rodríguez (presid.), Paulo Jorge Gouveia Simöes da Silva Oliveira (secret.), Albert Quintana Romero (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
OPA1 is a dynamin-related protein that is responsible for inner mitochondrial membrane fusion, essential for controlling mitochondrial cristae morphology, which impacts directly in OXPHOS efficiency, and is involved in mtDNA stability. In this study we have explored the effects of the hepatic depletion of OPA1 in mitochondrial function and in whole-body energy metabolism and the main conclusions of the basic characterization of mitochondria function, metabolic phenotyping of L-OPA1 KO mice model and mechanistic studies can be synthesized below: - OPA1 ablation results in mitochondrial dysfunction characterized by defects in mitochondrial respiratory capacity, mtDNA copy number reduction, disorganized cristae moprhology and mitochondrial proteostasis.
- Mitochondrial stress response associated to liver-specific OPA1 loss-of-function leads to FGF21 induction.
- OPA1 deficiency in liver causes improved glucose tolerance and protects against diet-induced obesity and insulin resistance possibly due to the action of FGF21.
- The absence of OPA1 in the cell leads to the activation of a mitochondrial stress response defined by the activation of mitochondrial-stress associated genes and UPRmt potentially mediated by ATF5.
Our results showed that OPA1 ablation leads to chronic mitochondrial stress and triggers the activation of UPRmt mediated by ATF5 in liver, suggesting that OPA1 has an important role in mitochondrial proteostasis. Moreover, our results demonstrate that the FGF21 induction relies on the activation of a mitochondrial response to stress caused by the depletion of OPA1, consequently, it improves the whole-body glucose homeostasis.
Based on the results of this PhD thesis, we propose that OPA1 deficiency leads to presence of chronic mitochondrial stress that triggers a mitochondrial stress response including the activation of UPRmt. We here hypothesize that this is the mechanism by which OPA1 deficiency in liver induces FGF21 induction, which eventually becomes systemic and leads to an improved glucose tolerance. Moreover, we propose ATF5 as the main mediator of UPRmt upon mitochondrial stress response associated OPA1 deletion in liver.
