Abstract
The transcription factor p73 has been demonstrated to play a significant role in survival and differentiation of neuronal stem cells. In this report, by employing comprehensive metabolic profile and mitochondrial bioenergetics analysis, we have explored the metabolic alterations in cortical neurons isolated from p73 N-terminal isoform specific knockout animals. We found that loss of the TAp73 or ΔNp73 triggers selective biochemical changes. In particular, p73 isoforms regulate sphingolipid and phospholipid biochemical pathway signaling. Indeed, sphinganine and sphingosine levels were reduced in p73-depleted cortical neurons, and decreased levels of several membrane phospholipids were also observed. Moreover, in line with the complexity associated with p73 functions, loss of the TAp73 seems to increase glycolysis, whereas on the contrary, loss of ΔNp73 isoform reduces glucose metabolism, indicating an isoform-specific differential effect on glycolysis. These changes in glycolytic flux were not reflected by parallel alterations of mitochondrial respiration, as only a slight increase of mitochondrial maximal respiration was observed in p73-depleted cortical neurons. Overall, our findings reinforce the key role of p73 in regulating cellular metabolism and point out that p73 exerts its functions in neuronal biology at least partially through the regulation of metabolic pathways.
Original language | English |
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Pages (from-to) | 3237-3250 |
Number of pages | 14 |
Journal | Molecular Neurobiology |
Volume | 55 |
Issue number | 4 |
Early online date | 6 May 2017 |
DOIs | |
Publication status | Published - 1 Apr 2018 |
Funding
Acknowledgments We would like to thank Dr. Ivano Amelio for helpful comments and suggestions. This work has been supported by the Medical Research Council, UK; grants from Associazione Italiana per la Ricerca contro il Cancro (AIRC): AIRC 2014 IG15653 (to G.M.), AIRC 5xmille MCO9979 (to G.M.), Fondazione Roma malattie Non trasmissibili Cronico-Degenerative (NCDS-2013-00000334) Grant (to G.M.).
Keywords
- Metabolism
- Neurons
- p53 family
- p73
- Sphingolipids
ASJC Scopus subject areas
- Neurology
- Cellular and Molecular Neuroscience