Autophagy (from the Greek self-eating) is a cellular mechanism which generates nutrients for the cell, primarily during times of starvation. Autophagy is also used to eliminate cell material that becomes damaged, leading to a periodic clean-up of the cell interior. Although it is a response by single cells, it is also very important for the health of an organism.
When autophagy is suppressed cells exhibit signs of oxidative damage because their dysfunctional mitochondria cannot be removed and continue to produce reactive oxygen species. Similarly, suppression of autophagy causes the build-up of mutant proteins that cause neurodegenerative disorders. Autophagy is also critical for the neonatal period: animals which lack autophagy die soon after birth because they cannot generate nutrients during that time. Finally, autophagy is critical for the extension of lifespan in all organisms studied, and is therefore a significant factor that affects healthy ageing.
The pathway of autophagy starts when a novel double membrane vesicle called an autophagosome is formed in the cell interior. We have shown that one of the signals for formation of autophagosomes is the synthesis of a lipid called PI3P which leads to formation of omegasomes. These are membrane extensions of the endoplasmic reticulum, from which some autophagosomes emerge. We are studying exactly how this happens, both in terms of signals and of how the intermediate structures eventually lead to an autophagosome.
A Milner Institute enabled project in collaboration with ALBORADA Drug Discovery Institute, MRC Mitochondrial Biology Unit, Astex, Eisai and Eli Lilly and Company is underway in my lab. We are examining by siRNA, chemical inhibition and overexpression a limited set of genes implicated in autophagy to determine their role in neurodegeneration. The last stage of this work will use iPSC-derived neuronal cells that we have developed in my lab and originate either from healthy donors or from Alzheimer’s patients. Read more at:
www.cam.ac.uk/business/neurodegeneration-collaboration www.cambridgeindependent.co.uk/business/win-win-as-milner-institute-brokers-pharma-trio-to-explore-9202021/
May 2024
Together with a number of University colleagues from Greece and abroad, we created a special supplement for the Kathimerini newspaper on ageing in many physiological settings. The title of the supplement, Makrozoia, means long life. The entire booklet is shown here.
November 2020
I was very happy to speak at the University of Michigan Protein Folding Diseases seminar series and this talk provides a nice summary of the current work in my lab.
The journal is now in its twenty-second year. Unlike many, perhaps most, other journals we have instituted various requirements to help ensure scientific clarity and reproducibility. Two of the most important requirements are the use of standardized nomenclature and the inclusion of specific ordering information for reagents. These are not arbitrary formatting issues - there are specific reasons they are required, which we will remind you of below. The point of this editor's corner is to explain that these requirements are now going to be enforced upon manuscript submission.
Professor Richard (Rick) Morimoto is the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for Biomedical Research at Northwestern University. He has made foundational contributions to our understanding of how cells respond to various stresses, and the role played in those responses by chaperones. Working across a variety of experimental models, from . to human neuronal cells, he has identified a number of important molecular components that sense and respond to stress, and he has dissected how stress alters cellular and organismal physiology. Together with colleagues, Professor Morimoto has coined the term "proteostasis" to signify the homeostatic control of protein expression and function, and in recent years he has been one of the leaders of a consortium trying to understand proteostasis in healthy and disease states. I took the opportunity to talk with Professor Morimoto about proteostasis in general, the aims of the consortium, and how autophagy is playing an important role in their research effort.
Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.