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 PGC1a. 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. Overall design: 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)