Universität zu Köln

Laboy Morales, Raymond A. ORCID: 0000-0002-0375-1550 (2022). Role of Myc/Mondo transcriptional network in metabolism and lifespan regulation. PhD thesis, Universität zu Köln.

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Abstract

The transcriptional complex MondoA/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in C. elegans. How do these pathways converge on this complex, and what are the upstream signals involved? This work sought to understand the upstream signals that regulate MML-1 localization, transcription, and longevity, using combined genetic, biochemical, omics, and light microscopy approaches. We found that an overall reduction in glucose metabolism decreases MML-1 localization in the nucleus and identified two hexokinase isozymes, hxk-1 and hxk-2, as strong positive regulators of MML-1 function. Upon knockdown, hexokinases reduce MML-1 nuclear localization and cause its redistribution to mitochondria and lipid droplets (LD). Interestingly, although both hexokinases decrease MML-1 nuclear function, we provide evidence that they do so through distinct mechanisms. On the one hand, we found that under hxk-1 knockdown, there is an increase in fatty acid metabolism, and pharmacological and genetic inhibition of mitochondrial -oxidation could rescue MML-1 localization. On the other hand, we found that oxoglutarate dehydrogenase complex (OGDC) and the pentose phosphate pathway (PPP) are important for decreasing MML 1 localization and function under hxk-2 knockdown. Analysis of the MML-1 interactome in different longevity backgrounds revealed that MML-1 associates with varying proteins from distinct cellular compartments, suggesting a role for MML-1 in integrating diverse organellar signals to the transcriptional response. In particular, we found many mitochondrial proteins, including the mitochondrial pyruvate carrier MPC-1 and the long-chain fatty acid acyl-CoA synthetase ACS-13, which is associated with both mitochondria and lipid droplets. Both candidates showed a degree of cellular co-localization and functional interaction with MML-1, suggesting that these proteins could cooperate with MML-1 in connecting metabolism and transcription.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Laboy Morales, Raymond A. raymond.laboy.morales@gmail.com orcid.org/0000-0002-0375-1550 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-611301
Date:	2 May 2022
Publisher:	University of Cologne
Place of Publication:	Cologne
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language MondoA UNSPECIFIED mitochondria English metabolism English transcription factor English aging English
Date of oral exam:	28 April 2022
Referee:	Name Academic Title Antebi, Adam Dr. Cabreiro, Filipe Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/61130