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Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

ABSTRACT: Metabolic reprograming is one of the hallmarks of tumorigenesis. Using a combination of multi-omics, here we show that nuclear myosin 1 (NM1) serves a key regulator of cellular metabolism. As part of nutrient-sensing PI3K/Akt/mTOR pathway, NM1 forms a positive feedback loop with mTOR, and directly affects mitochondrial oxidative phosphorylation via transcriptional regulation of mitochondrial transcription factors TFAM and PGC1α. NM1 depletion leads to a suppression of PI3K/Akt/mTOR pathway, underdevelopment of mitochondria inner cristae and redistribution of mitochondria within a cell, which is associated with reduced expression of oxidative phosphorylation genes, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics. This leads to a metabolic reprogramming of NM1 KO cells from oxidative phosphorylation to aerobic glycolysis and with that associated metabolomic profile typical for cancer cells, namely, increased amino acid-, fatty acid-, and sugar metabolism, and increase in glucose uptake, lactate production and intracellular acidity. We show that NM1 KO cells are able to form solid tumors in a nude mouse model even though they have supressed PI3K/Akt/mTOR signalling pathway suggesting that the metabolic switch towards aerobic glycolysis provide a sufficient signal for carcinogenesis. We suggest that NM1 plays a key role as tumor suppressor and that NM1 depletion may be partly responsible for the Warburg effect at the early onset of tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE236679 | GEO | 2023/07/13

REPOSITORIES: GEO

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Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H). This model is described in the article: Computational Modelling of the Metabolic States Regulated by the Kinase Akt. Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L. Frontiers in Systems Biology. 2012 Oct 13 Abstract: Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism. This model is hosted on BioModels Database and identified by: MODEL1210150000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

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