ESR10: “The role of Opa1-dependent mitochondrial cristae remodelling in age-related diseases”

UniPD (L. Scorrano group): The role of Opa1-dependent mitochondrial cristae remodelling in age-related diseases

i. Objective of research: To characterize how ameliorated cristae shape is linked to healthy ageing at the cellular and systemic levels.

ii. Current state of the art: Mitochondrial dysfunction and dysmorphology is associated with multiple cellular alterations, including ageing. We recently discovered that the cristae remodeling pathway controlled by the mitochondria-shaping protein Opa1 counteracts age-related sarcopenia1. Moreover, we showed that a reduction in muscle Opa1 levels in the elderly is associated with loss of muscle force and in the mouse with a systemic ageing response mediated by muscle production and secretion of very high levels of Fgf212. However, it remains unclear how changes in cristae shape are monitored by the cell and the organism or whether ameliorated cristae shape counteracts tissue dysfunction in ageing. Here, we wish to characterize the molecular signals of altered cristae shape and ameliorate cristae morphology in ageing.

iii. Research methodology and approach: We will investigate how cristae shape changes are signalled to induce systemic ageing; and whether ameliorated cristae shape counteracts tissue dysfunction in ageing by testing if identified epigenetic and small molecule activators of Opa1 phenocopy Opa1 overexpression. First, we will explore the local and systemic consequences of a novel Epac1-Rap1 signalling pathway identified by unbiased RNA-seq across multiple models of altered mitochondrial cristae, by genetic and pharmacological inhibition of the apical components localized in preliminary experiments in mitochondria. Second, by using models of inducible Opa1 deletion in skeletal muscle, we will exploit inhibition of this Epac1-Rap1 pathway to counteract Fgf21 production and systemic ageing. In a complementary approach, we will test if Opa1 overexpression counteracts ageing in the well-established nematode C. elegans model. Finally, we will test if novel epigenetic and small molecules identified in our laboratory to upregulate or activate Opa1 counteract muscle loss, accumulation of fat and metabolic dysfunction associated with ageing.

iv. Originality and innovative aspects of the ESR project: Using a combination of cellular and organismic models, we propose to dissect the pathways and functional contribution of mitochondrial cristae shape changes in ageing in vivo; this will allow us to develop rationalized intervention strategies to ameliorate mitochondrial function in age-related diseases.

v. Integration of the ESR project to the overall research programme: Our ESR will work on mitophagy in C. elegans (with the Tavernarakis group) and on small molecule testing (with the Amazentis group).