Award details

How autophagy and related processes are coordinated and important in adaption to changed nutrient availability and cell damage

Reference	BBS/E/B/000C0434
Principal Investigator / Supervisor	Dr Simon Cook
Co-Investigators / Co-Supervisors	Dr Michael Coleman, Dr Oliver Florey, Dr Phillip Hawkins, Dr Nicholas Ktistakis, Dr Hayley Sharpe, Professor Len Stephens, Dr Heidi Welch
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	5,452,381
Status	Current
Type	Institute Project
Start date	01/04/2017
End date	31/03/2023
Duration	59 months

Abstract

The increase in life span of model organisms subjected to DR is dependent on autophagy83 but the exact molecular mechanisms linking autophagy to ageing remain elusive. A major complication is that autophagy is part of one of the hallmarks of ageing namely loss of proteostasis while also contributing to several others such as deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence and stem cell exhaustion. Of note, up-regulation of autophagy by transgenic expression of ATG5 in mice extends health and life span2. The core process of autophagy is the generation of a double membrane bounded organelle that can engulf cell constituents and traffic them into the lysosomal compartment for recycling. Two protein machines control the initiation of autophagy, the ULK and Vps34 (class III PI3K) complexes. Together they remodel the ER to generate early autophagosomes that expand in an LC3- lipidation-dependent fashion. Autophagy operates in different contexts. If nutrients are scarce non-selective autophagy is induced by activation of AMPK and inactivation of mTORC1 and engulfs cytoplasm and/or organelles in autophagosomes of diverse size. There are forms of autophagy that proceed in the presence of ample nutrients (“selective” autophagy, eg, mitophagy (autophagy of mitochondria), are targeted by cargo-selective autophagic receptors and appear to be insensitive to changes in mTORC1 or AMPK activity. Both nutrient-supply-sensitive and “selective” autophagy are probably important for dietary-restriction-induced life span extension. Recent work has shown that molecular components of the autophagy pathway, including the machinery that lipidates LC3, have roles in other cell processes that can internalise and deliver extracellular material to lysosomes, eg phagocytosis, entosis and macropinocytosis. The molecular mechanisms that coordinate this non-canonical use of the autophagy apparatus, their roles in cell biology and how they dovetail with conventional autophagy are unknown.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search