Universität zu Köln

Kim, Jun Yong ORCID: 0000-0003-1810-6615 (2022). Mitochondrial plasticity implicates their new purpose in therapy-induced senescence. PhD thesis, Universität zu Köln.

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Abstract

Cellular senescence and mitochondrial dysfunction are regarded as pillars of aging and age-related diseases such as cancer. As a result, there have been great efforts to understand the role of the two phenomena in such pathological settings. However, the exact relationship between the two is not fully understood due in part to conflicting results. A thorough understanding of their relationship warrants revealing greater therapeutic targets in age-related diseases. Here, I report mitochondrial states with their accurate quantity in a senescent cell. Mitochondria were found to be bioenergetically hypoactive in senescent cells demonstrated by lower membrane potential, lower superoxide level, and lower respiration compared to proliferating cells. However, a profound increase of mitochondrial volume in a senescent cell led to enhanced outputs of the bioenergetic parameters on a cellular base. This largely resolves the paradoxical states of mitochondria in senescent cells and agrees with their age-related dysfunctions. In subsequent analyses combined with time-resolved quantitative proteomics and metabolomics, it was found that metabolic rewiring is the main signature amongst all mitochondrial pathways in senescent cells. In detail, branched-chain amino acid catabolism was increased while one carbon-folate metabolism was rapidly blocked upon the induction of cellular senescence. Such rewired mitochondrial metabolisms orchestrated a synthesis of non-essential amino acids, nucleotides, and translation of mitochondrial RNAs in senescent cells. Besides, a mitochondrial orphan gene OCIAD2 was identified as a pan-senescence marker. The inner mitochondrial membrane protein OCIAD2 regulated the formation of perinuclear mitochondrial clumps in senescent cells. Moreover, bulk RNA-seq analyses discovered its potential crosstalk with TGF-b signaling in senescent cells. However, OCIAD2 neither regulated respiration and superoxide generation, nor oxidation of glucose, glutamine, and fatty acids in mitochondria of senescent cells. Thus, the function of OCIAD2 remains to be determined other than those. These data collectively demonstrate the mitochondrial plasticity in senescent cells and warrant future investigation into their regulatory roles in senescent cells.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Kim, Jun Yong baizzang1@gmail.com orcid.org/0000-0003-1810-6615 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-618720
Date:	26 September 2022
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Natural sciences and mathematics Life sciences
Uncontrolled Keywords:	Keywords Language cellular senescence English mitochondrial reprogramming English branched-chain amino acid metabolism English one carbon folate metabolism English mitochondrial translation English mitochondrial bioenergetics English therapy-induced senescence English
Date of oral exam:	16 August 2022
Referee:	Name Academic Title Langer, Thomas Prof. Dr. Beyer, Andreas Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/61872