Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Venit, T.; Sapkota, O.; Abdrabou, W. S.; Loganathan, P.; Pasricha, R.; Mahmood, S. R.; El Said, N.; Thomas, S.; Idaghdour, Y.; Magzoub, M.; Percipalle, P.

doi:10.1101/2022.06.30.498328

bioRxiv · 10.1101/2022.06.30.498328

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Venit, T.·Sapkota, O.·Abdrabou, W. S.·Loganathan, P.·Pasricha, R.·Mahmood, S. R.·El Said, N.·Thomas, S.·Idaghdour, Y.·Magzoub, M.·Percipalle, P.

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Abstract

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Using a combination of multi-omics, here we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. As part of the nutrient-sensing PI3K/Akt/mTOR pathway, NM1 forms a positive feedback loop with mTOR and directly affects mitochondrial oxidative phosphorylation (OXPHOS) via transcriptional regulation of mitochondrial transcription factors TFAM and PGC1. NM1 depletion leads to suppression of PI3K/Akt/mTOR pathway, underdevelopment of mitochondria inner cristae, and redistribution of mitochondria within the cell, which is associated with reduced expression of OXPHOS genes, decreased mitochondrial DNA copy number and deregulated mitochondrial dynamics. This leads to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis and with a metabolomic profile typical for cancer cells, namely, increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. We show that NM1 KO cells form solid tumors in a nude mouse model even though they have suppressed the PI3K/Akt/mTOR signaling pathway suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient signal for carcinogenesis. We suggest that NM1 plays a key role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the early onset of tumorigenesis.

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Venit, T., Sapkota, O., Abdrabou, W. S., Loganathan, P., Pasricha, R., Mahmood, S. R., El Said, N., Thomas, S., Idaghdour, Y., Magzoub, M., Percipalle, P.. 2022-07-02. Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice. https://doi.org/10.1101/2022.06.30.498328

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