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

Abstract

SummaryMetabolic 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 PGC1α. 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.

Comparative framework and adaptation of ACME HS approach to single cell isolation from fresh-frozen endocrine tissues

“…Overall, we demonstrated a comparable representation of the major cell types, subpopulations, and functional states in ACME HS and enzymatic methods, while the single nuclei-based protocol performed significantly much worse. Our data thus corroborate previous observations on the principal differences of scRNA vs snRNA profiles, particularly in terms of cytoplasm-associated signatures, including those associated with cellular metabolism [34], protein synthesis and mRNA processing [35], [36], the processes being particularly important for tumorigenesis [37], [38], with a proper representation thereof being critical for obtaining of the biologically relevant data in the studies of human neoplastic diseases.…”

Nuclear Myosin 1 regulates platelet activation and immune response in mice

“…The regulation of this metabolic switch is still poorly understood but it is getting gradual attention as it is associated with many metabolic disorders. Recently, we discovered that Nuclear Myosin 1 plays a critical role in this process and its mutation or deletion leads to a metabolic switch from oxidative phosphorylation to glycolysis and subsequent tumorigenesis in mice (Venit et al, 2022). Because of these observations, we hypothesized that NM1 may be a general factor regulating the switch between oxidative phosphorylation and glycolysis in multiple tissues such as the bone marrow.…”

“…This negatively regulates mitochondrial oxidative phosphorylation and leads to metabolic reprograming towards glycolysis, a hall mark of cancer cells. Indeed, NM1 knockout (KO) cells are able to form solid tumors in a nude mouse model even though they have suppressed the PI3K/Akt/mTOR signalling pathway suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient signal for carcinogenesis (Venit et al, 2022). The metabolic switch from oxidative phosphorylation to glycolysis caused by NM1 deletion is not only affecting tumorigenic potential of the somatic cells but it may also affect pluripotent stem cells which under normal conditions keep the glycolytic type of metabolism and only change to oxidative phosphorylation during differentiation.…”