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

Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform.
Zachari M, Gudmundsson SR, Li Z, Manifava M, Shah R, Smith M, Stronge J, Karanasios E, Piunti C, Kishi-Itakura C, Vihinen H, Jokitalo E, Guan JL, Buss F, Smith AM, Walker SA, Eskelinen EL, Ktistakis NT

The dynamics and coordination between autophagy machinery and selective receptors during mitophagy are unknown. Also unknown is whether mitophagy depends on pre-existing membranes or is triggered on the surface of damaged mitochondria. Using a ubiquitin-dependent mitophagy inducer, the lactone ivermectin, we have combined genetic and imaging experiments to address these questions. Ubiquitination of mitochondrial fragments is required the earliest, followed by auto-phosphorylation of TBK1. Next, early essential autophagy proteins FIP200 and ATG13 act at different steps, whereas ULK1 and ULK2 are dispensable. Receptors act temporally and mechanistically upstream of ATG13 but downstream of FIP200. The VPS34 complex functions at the omegasome step. ATG13 and optineurin target mitochondria in a discontinuous oscillatory way, suggesting multiple initiation events. Targeted ubiquitinated mitochondria are cradled by endoplasmic reticulum (ER) strands even without functional autophagy machinery and mitophagy adaptors. We propose that damaged mitochondria are ubiquitinated and dynamically encased in ER strands, providing platforms for formation of the mitophagosomes.

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Developmental cell, , 1878-1551, , 2019

PMID: 31353311

Who plays the ferryman: ATG2 channels lipids into the forming autophagosome.
Ktistakis NT

Expansion of the autophagosomal membrane requires a mechanism to supply lipids while excluding most membrane proteins. In this issue, Valverde et al. (2019. https://doi.org/10.1083/jcb.201811139) identify ATG2, a member of the autophagy-related protein family, as a lipid transfer protein and provide important novel insights on how autophagosomes grow.

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The Journal of cell biology, , 1540-8140, , 2019

PMID: 31076453

ER platforms mediating autophagosome generation.
Ktistakis NT

The origin of the autophagosomal membrane started to be debated by scientists working in the field within one year of the modern definition of autophagy in 1963. There is now converging evidence from older and newer studies that the endoplasmic reticulum is involved in formation of autophagosomes. Thus, it is possible to trace from early morphological work - done without the benefit of molecular descriptions - to recent studies - dissecting how specific proteins nucleate autophagosome biogenesis - a long series of experimental findings that are beginning to answer the 55-year old question with some confidence. The view that has emerged is that specialised regions of the endoplasmic reticulum, in dynamic cross talk with most intracellular organelles via membrane contact sites, provide a platform for autophagosome biogenesis.

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Biochimica et biophysica acta. Molecular and cell biology of lipids, , 1879-2618, , 2019

PMID: 30890442