Life Sciences Research for Lifelong Health

Nicholas Ktistakis

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.

Latest Publications

Molecular definitions of autophagy and related processes.
Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M, Harper JW, Jäättelä M, Johansen T, Juhasz G, Kimmelman AC, Kraft C, Ktistakis NT, Kumar S, Levine B, Lopez-Otin C, Madeo F, Martens S, Martinez J, Melendez A, Mizushima N, Münz C, Murphy LO, Penninger JM, Piacentini M, Reggiori F, Rubinsztein DC, Ryan KM, Santambrogio L, Scorrano L, Simon AK, Simon HU, Simonsen A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Kroemer G

Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.

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The EMBO journal, , 1460-2075, , 2017

PMID: 28596378

Phospholipase D activity couples plasma membrane endocytosis with retromer dependent recycling.
Thakur R, Panda A, Coessens E, Raj N, Yadav S, Balakrishnan S, Zhang Q, Georgiev P, Basak B, Pasricha R, Wakelam MJ, Ktistakis NT, Padinjat R

During illumination, the light sensitive plasma membrane (rhabdomere) of Drosophila photoreceptors undergoes turnover with consequent changes in size and composition. However the mechanism by which illumination is coupled to rhabdomere turnover remains unclear. We find that photoreceptors contain a light-dependent phospholipase D (PLD) activity. During illumination, loss of PLD resulted in an enhanced reduction in rhabdomere size, accumulation of Rab7 positive, rhodopsin1-containing vesicles (RLVs) in the cell body and reduced rhodopsin protein. These phenotypes were associated with reduced levels of phosphatidic acid, the product of PLD activity and were rescued by reconstitution with catalytically active PLD. In wild type photoreceptors, during illumination, enhanced PLD activity was sufficient to clear RLVs from the cell body by a process dependent on Arf1-GTP levels and retromer complex function. Thus, during illumination, PLD activity couples endocytosis of RLVs with their recycling to the plasma membrane thus maintaining plasma membrane size and composition.

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eLife, 5, 2050-084X, , 2016

PMID: 27848911

Assembly of early machinery for autophagy induction: novel insights from high resolution microscopy.
Ktistakis NT, Walker SA, Karanasios E

Oncotarget, , 1949-2553, , 2016

PMID: 27829241

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Keywords

amino acid sensing
autophagy
cell biology
developmental biology
mtor signalling
super resolution microscopy

Group Members

Latest Publications

Molecular definitions of autophagy and related processes.

Galluzzi L, Baehrecke EH, Ballabio A

The EMBO journal
1460-2075: (2017)

PMID: 28596378

Assembly of early machinery for autophagy induction: novel insights from high resolution microscopy.

Ktistakis NT, Walker SA, Karanasios E

Oncotarget
1949-2553: (2016)

PMID: 27829241

Dynamics of mTORC1 activation in response to amino acids.

Manifava M, Smith M, Rotondo S

eLife
5 2050-084X: (2016)

PMID: 27725083

Characterization of Atg38 and NRBF2, a fifth subunit of the autophagic Vps34/PIK3C3 complex.

Ohashi Y, Soler N, García Ortegón M

Autophagy
1554-8635:0 (2016)

PMID: 27630019

Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles.

Karanasios E, Walker SA, Okkenhaug H

Nature communications
7 2041-1723:12420 (2016)

PMID: 27510922

Digesting the Expanding Mechanisms of Autophagy.

Ktistakis NT, Tooze SA

Trends in cell biology
1879-3088: (2016)

PMID: 27050762

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).

Klionsky DJ, Abdelmohsen K, Abe A

Autophagy
12 1554-8635:1-222 (2016)

PMID: 26799652

Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes.

Rostislavleva K, Soler N, Ohashi Y

Science (New York, N.Y.)
350 1095-9203:aac7365 (2015)

PMID: 26450213

ERES: sites for autophagosome biogenesis and maturation?

Sanchez-Wandelmer J, Ktistakis NT, Reggiori F

Journal of cell science
128 1477-9137:185-192 (2015)

PMID: 25568152

Live-cell imaging for the assessment of the dynamics of autophagosome formation: Focus on early steps.

Karanasios E, Ktistakis NT

Methods (San Diego, Calif.)
1095-9130: (2014)

PMID: 25498007