ò

Ktistakis Group

Ktistakis Group
Ktistakis Group
Nicholas Ktistakis
Group Leader
Ktistakis Group

Research Summary

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:



/

 

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.

Latest Publications

Chen X, Tsvetkov AS, Shen HM, Isidoro C, Ktistakis NT, Linkermann A, Koopman WJH, Simon HU, Galluzzi L, Luo S, Xu D, Gu W, Peulen O, Cai Q, Rubinsztein DC, Chi JT, Zhang DD, Li C, Toyokuni S, Liu J, Roh JL, Dai E, Juhasz G, Liu W, Zhang J, Yang M, Liu J, Zhu LQ, Zou W, Piacentini M, Ding WX, Yue Z, Xie Y, Petersen M, Gewirtz DA, Mandell MA, Chu CT, Sinha D, Eftekharpour E, Zhivotovsky B, Besteiro S, Gabrilovich DI, Kim DH, Kagan VE, Bayir H, Chen GC, Ayton S, Lünemann JD, Komatsu M, Krautwald S, Loos B, Baehrecke EH, Wang J, Lane JD, Sadoshima J, Yang WS, Gao M, Münz C, Thumm M, Kampmann M, Yu D, Lipinski MM, Jones JW, Jiang X, Zeh HJ, Kang R, Klionsky DJ, Kroemer G, Tang D Signalling

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.

+view abstract Autophagy, PMID: 38442890

Open Access
Renna FJ, Enriqué Steinberg JH, Gonzalez CD, Manifava M, Tadic MS, Orquera T, Vecino CV, Ropolo A, Guardavaccaro D, Rossi M, Ktistakis NT, Vaccaro MI Signalling

Autophagy is a tightly regulated catabolic process involved in the degradation and recycling of proteins and organelles. Ubiquitination plays an important role in the regulation of autophagy. Vacuole Membrane Protein 1 (VMP1) is an essential autophagy protein. The expression of VMP1 in pancreatic cancer stem cells carrying the activated Kirsten rat sarcoma viral oncogene homolog (KRAS) triggers autophagy and enables therapy resistance. Using biochemical and cellular approaches, we identified ubiquitination as a post-translational modification of VMP1 from the initial steps in autophagosome biogenesis. VMP1 remains ubiquitinated as part of the autophagosome membrane throughout autophagic flux until autolysosome formation. However, VMP1 is not degraded by autophagy, nor by the ubiquitin-proteasomal system. Mass spectrometry and immunoprecipitation showed that the cell division cycle protein cdt2 (Cdt2), the substrate recognition subunit of the E3 ligase complex associated with cancer, cullin-RING ubiquitin ligase complex 4 (CRL4), is a novel interactor of VMP1 and is involved in VMP1 ubiquitination. VMP1 ubiquitination decreases under the CRL inhibitor MLN4924 and increases with Cdt2 overexpression. Moreover, VMP1 recruitment and autophagosome formation is significantly affected by CRL inhibition. Our results indicate that ubiquitination is a novel post-translational modification of VMP1 during autophagy in human tumor cells. VMP1 ubiquitination may be of clinical relevance in tumor-cell-therapy resistance.

+view abstract International journal of molecular sciences, PMID: 37629161

Murphy LO, Ktistakis NT Signalling

As a maturing field that continues to provide fundamental insights into cell physiology, autophagy is also beginning to attract considerable interest from the biotechnology/pharmaceutical sector. For this Editor's corner, I thought it would be both useful and interesting to talk with somebody who has spent a lot of time in the commercial sphere, working on autophagy and related processes. I was fortunate that Dr. Leon Murphy, Chief Scientific Officer at Casma therapeutics, was willing and able to answer my questions. In addition to his insights on the commercial interest for autophagy, Dr. Murphy also shared his personal experience on the scientific life working in large and small pharmaceutical companies.

+view abstract Autophagy, PMID: 37255335

Group Members

Nicholas Ktistakis

Group Leader

Nikhita Annaiyappa

Visiting Scientist

Adelyne Chan

Research Assistant

Simay Kayahan

Visiting Scientist

Maria Manifava

Senior Research Scientist

Aled Parry

Visiting Scientist

Zoe Shu

Visiting Student

Femke Speelman-Rooms

Visiting Student