Marianna Holczer 1, Bence Hajdú 2, Prof. Dr. Gábor Bánhegyi 3, Dr. Orsolya Kapuy 4
1,2,3,4 Department of Medical Chemistry, Molecular Biology and Pathobiochemistry
Introduction: The autophagy is tightly regulated by mTOR and AMPK kinases. AMPK is able to promote autophagy by phosphorylating ULK1, the key inducer of autophagosome formation, meanwhile mTOR down-regulates the self-eating process via ULK1 under nutrient rich condition.
Aims: In our opinion, there is an essential double negative feedback loop between mTOR and AMPK kinases. Namely, not only AMPK down-regulates mTOR, but mTOR also inhibits AMPK. We claim that this inhibition is required for keeping AMPK inactive at physiological conditions.
The aim of the present study is to explore the regulatory connection between mTOR and AMPK.
Method: We approach our scientific analysis from a systems biological perspective by using both theoretical and molecular biological techniques. For molecular biological experiments HEK293T cell line is used, meanwhile the dynamical characteristic of the regulatory network is described by mathematical modelling.
Results: We claim that, the ULK1-regulated autophagy is always preceded by AMPK activation. AMPK is essential to induce autophagy, but not sufficient to maintain it. AMPK activation is followed by ULK1 induction, and it has a key role in keeping autophagy active. Either mTOR hyperactivation (via TSC1/2 down-regulation) or ULK1 depletion verify that AMPK-mTOR double negative feedback loop is crucial for the proper dynamical features of the control network. Our computer simulations further confirm the dynamical characteristic of AMPK-mTOR-ULK1 regulated cellular stress response mechanism.
Conclusion: Our systems biological analysis improves the understanding of the molecular basis of several cellular stress related diseases (such as neurodegenerative diseases) and might help to promote advanced therapies in the near future, too.
This work was supported by the ÚNKP-18-3-I-SE-19 New National Excellence Program of the
Ministry of Human Capacities.
Doctoral School: Molecular Medicine
Supervisor: Orsolya Kapuy-Mészáros
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