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

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. RNA seq of tumors derived from NM1 KO mouse embryonic fibroblasts and tumors derived from NM1 KO mouse embryonic fibroblast with reintroduced NM1 (KO+NM1)