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ERC

MITOSIGAGE Report Summary

Project ID: 281691
Funded under: FP7-IDEAS-ERC
Country: Spain

Final Report Summary - MITOSIGAGE (Mitochondrial crosstalk signalling in the regulation of ageing)

Understanding the complex and fascinating biological process of ageing is a challenging objective of fundamental importance given the rate at which society ages. Our current understanding of ageing is limited to a few molecular pathways that include insulin/IGF-1 signalling (IIS), dietary restriction, TOR signalling and mitochondrial function. However, how the different molecular pathways modulating ageing are interconnected is not well understood. It is generally believed that mitochondria and IIS regulate lifespan independently of each other. Nonetheless, the interaction of mitochondria with cellular signalling pathways regulating ageing appears to be more complex than previously anticipated. This is reflected by the intriguing effect of the mitochondrial prohibitin (PHB) complex on longevity. Prohibitins consist of two subunits (PHB-1 and PHB-2) that together form a high-molecular-weight complex in the mitochondrial inner membrane. PHB depletion in an otherwise wild-type animal shortens lifespan, while it tremendously increases the lifespan of long-lived insulin receptor mutants, dietary-restricted animals and mitochondrial mutants among others.
This project aimed at understanding the opposing effect of PHB on the ageing process by focusing our efforts on its interaction with the IIS pathway. For this, we undertook an unbiased multidisciplinary approach that involves the development of genome-wide RNAi screenings to find regulators of the responses to PHB depletion in both wild type and IIS mutants, as well as a metabolomics approach to pinpoint the molecular pathways and the players responsible for such intriguing opposite ageing phenotype.
On the basis of the genetic screens, on the one hand, we have screened for kinases implicated in the metabolic response to PHB depletion. We have focused our efforts on the characterisation of Glycogen Synthase Kinase 3, a highly conserved and pleiotropic kinase, which differentially regulates metabolism and ageing in PHB and IIS deficient animals. On the other hand, genome-wide RNAi screens have provided a complete view of the processes involved in modulating the mitochondrial stress response upon PHB depletion in wild type and IIS mutant animals. We have identified epigenetic mechanisms that open new avenues of research. In addition, aiming at better dissecting the molecular interaction of PHB with the IIS pathway. We demonstrate that SGK-1, a downstream kinase of the IIS, acts in parallel to the IIS, within the conserved mechanistic Target Of Rapamycin complex 2 (mTORC2), to modulate PHB mediated lifespan, mitochondrial biogenesis and stress responses. These results highlight the complexity of the crosstalk between mitochondria and cellular networks in the regulation of longevity and stress response and shed light on the cellular signalling pathways involved in mitochondrial maintenance.
We have also considerably advanced our understanding of the metabolic fingerprints associated with PHB depletion in otherwise wild-type animals and in IIS mutants. We have combined metabolomics and RNAseq data during ageing to generate metabolic network models that suggest which metabolic adjustments are responsible for the opposing ageing phenotypes caused by PHB depletion.
In sum, the mutually reinforcing approaches used have proved the correctness of our fundamental starting idea that the interaction of mitochondria with cellular signalling networks to fine tune metabolism is more complex that previously suspected. Our efforts are providing valuable insights to understand the complexity of the ageing process.

Reported by

UNIVERSIDAD PABLO DE OLAVIDE
Spain
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