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

Targeting of early endosomes by autophagy facilitates EGFR recycling and signalling.
Fraser J, Simpson J, Fontana R, Kishi-Itakura C, Ktistakis NT, Gammoh N

Despite recently uncovered connections between autophagy and the endocytic pathway, the role of autophagy in regulating endosomal function remains incompletely understood. Here, we find that the ablation of autophagy-essential players disrupts EGF-induced endocytic trafficking of EGFR. Cells lacking ATG7 or ATG16L1 exhibit increased levels of phosphatidylinositol-3-phosphate (PI(3)P), a key determinant of early endosome maturation. Increased PI(3)P levels are associated with an accumulation of EEA1-positive endosomes where EGFR trafficking is stalled. Aberrant early endosomes are recognised by the autophagy machinery in a TBK1- and Gal8-dependent manner and are delivered to LAMP2-positive lysosomes. Preventing this homeostatic regulation of early endosomes by autophagy reduces EGFR recycling to the plasma membrane and compromises downstream signalling and cell survival. Our findings uncover a novel role for the autophagy machinery in maintaining early endosome function and growth factor sensing.

+ View Abstract

EMBO reports, , 1469-3178, e47734, 2019

PMID: 31448519

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.

+ View Abstract

Developmental cell, , 1878-1551, , 2019

PMID: 31353311

Autophagy, Inflammation, and Metabolism (AIM) Center in its second year.
Deretic V, Prossnitz E, Burge M, Campen MJ, Cannon J, Liu KJ, Liu M, Hall P, Sklar LA, Allers L, Mariscal L, Garcia SA, Weaver J, Baehrecke EH, Behrends C, Cecconi F, Codogno P, Chen GC, Elazar Z, Eskelinen EL, Fourie B, Gozuacik D, Hong W, Jo EK, Johansen T, Juhász G, Kimchi A, Ktistakis N, Kroemer G, Mizushima N, Münz C, Reggiori F, Rubinsztein D, Ryan K, Schroder K, Shen HM, Simonsen A, Tooze SA, Vaccaro M, Yoshimori T, Yu L, Zhang H, Klionsky DJ

The NIH-funded center for autophagy research named Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center is now completing its second year as a working center with a mission to promote autophagy research locally, nationally, and internationally. The center has thus far supported a cadre of 6 junior faculty (mentored PIs; mPIs) at a near-R01 level of funding. Two mPIs have graduated by obtaining their independent R01 funding and 3 of the remaining 4 have won significant funding from NIH in the form of R21 and R56 awards. The first year and a half of setting up the center has been punctuated by completion of renovations and acquisition and upgrades for equipment supporting autophagy, inflammation and metabolism studies. The scientific cores usage, and the growth of new studies is promoted through pilot grants and several types of enablement initiatives. The intent to cultivate AIM as a scholarly hub for autophagy and related studies is manifested in its Vibrant Campus Initiative, and the Tuesday AIM Seminar series, as well as by hosting a major scientific event, the 2019 AIM symposium, with nearly one third of the faculty from the International Council of Affiliate Members being present and leading sessions, giving talks, and conducting workshop activities. These and other events are often videostreamed for a worldwide scientific audience, and information about events at AIM and elsewhere are disseminated on Twitter and can be followed on the AIM web site. AIM intends to invigorate research on overlapping areas between autophagy, inflammation and metabolism with a number of new initiatives to promote metabolomic research. With the turnover of mPIs as they obtain their independent funding, new junior faculty are recruited and appointed as mPIs. All these activities are in keeping with AIM's intention to enable the next generation of autophagy researchers and help anchor, disseminate, and convey the depth and excitement of the autophagy field.

+ View Abstract

Autophagy, 15, 1554-8635, 1829-1833, 2019

PMID: 31234750

Group Members

Latest Publications

Targeting of early endosomes by autophagy facilitates EGFR recycling and signalling.

Fraser J, Simpson J, Fontana R

EMBO reports
1469-3178:e47734 (2019)

PMID: 31448519

Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform.

Zachari M, Gudmundsson SR, Li Z

Developmental cell
1878-1551: (2019)

PMID: 31353311

Autophagy, Inflammation, and Metabolism (AIM) Center in its second year.

Deretic V, Prossnitz E, Burge M

Autophagy
15 1554-8635:1829-1833 (2019)

PMID: 31234750

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

Ktistakis NT

The Journal of cell biology
1540-8140: (2019)

PMID: 31076453

ER platforms mediating autophagosome generation.

Ktistakis NT

Biochimica et biophysica acta. Molecular and cell biology of lipids
1879-2618: (2019)

PMID: 30890442

Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation.

Kumar S, Gu Y, Abudu YP

Developmental cell
1878-1551: (2019)

PMID: 30827897

Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells.

Bussi C, Peralta Ramos JM, Arroyo DS

Journal of cell science
1477-9137: (2018)

PMID: 30404831

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