Universität zu Köln

Chandragiri, Srikanth (2023). Proteolytic rewiring of the mitochondria in hypoxia. PhD thesis, Universität zu Köln.

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Abstract

Molecular oxygen sustains intracellular bioenergetics and is consumed by more than 400 biochemical reactions, making it essential for most species on Earth. Reduced oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in inflammation, bacterial infection, cardiovascular defects, wounds, and cancer. Despite the fundamental importance of oxygen in human physiology and disease, we currently lack a complete understanding of how the mitochondrial proteome adapts fluctuations in oxygen tensions. We recently identify a mTORC1-LIPIN1-lipid signaling cascade that activates the i-AAA protease YME1L in hypoxia to ensure pyrimidine synthesis. Here, we determined protein turnover rates of mitochondrial proteins in hypoxia. The mitochondrial m-AAA protease AFG3L2 was found to reshape the mitochondrial matrix and inner mitochondrial membrane (IMM) proteome in hypoxia. This proteolytic rewiring affects various biological pathways, such as lipid metabolism, protein import, OXPHOS and metabolism. Hypoxia is one of the main stressors of the mTORC1, we investigated the role of mTORC1 in AFG3L2 dependent proteolytic rewiring. In nutrient starvation mTORC1 is inhibited and activates AFG3L2-dependent proteolytic rewiring, whereas active mTORC1 inhibits AFG3L2 activity. NCLX is a Na+/Ca2+ exchanger, which effluxes Ca2+ from the matrix in exchange for Na+ from the intermembrane space and loss of NCLX activates AFG3L2 -dependent proteolysis. We show that in hypoxia changes protein turnover, the mitochondrial m-AAA protease AFG3L2 reshapes the mitochondrial proteome to adapt to hypoxia.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Chandragiri, Srikanth Schandragiri@age.mpg.de UNSPECIFIED UNSPECIFIED
Contributors:	Contribution Name Email Author Chandragiri, PhD SChandragiri@age.mpg.de
URN:	urn:nbn:de:hbz:38-704235
Date:	11 May 2023
Publisher:	Srikanth
Place of Publication:	Cologne
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Hypoxia, mTORC1, Calcuim, AFG3L2, Mitochondria, Proteolytic rewiring, Starvation, Proteostasis UNSPECIFIED
Date of oral exam:	23 January 2023
Referee:	Name Academic Title Thomas, Langer Director Thorsten, Hope Professor Jan, Riemer Professor
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/70423