MTOR- and HIF-1a–mediated aerobic glycolysis

Starvation therapy posts an advantage of having lower toxicity than conventional radiation and chemotherapy. Recent studies showed that starvation of arginine, asparagine, cysteine, leucine, and glutamine seems to provide special killing of tumor cells. Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. Here, we show that arginine depletion leads to mitochondrial dysfunction and then atypical cellular death.

First of all, Argininosuccinate synthetase (Ass1), an enzyme for intracellular arginine synthesis has reduced expression in many cancer types including prostate cancer.

Next, we build an AAS1 KO model, further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, leading to DNA damage accumulation

Another finding in this paper is the high level of giant autophagosomes and autolysosomes encapsulating the leaked DNA in the ADI-PEG20–treated dying cells. Moreover, these cells were able to maintain cell adhesion in culture, suggesting that the DNA leakage did not take place after cell death.

Arginine and asparagine depletion probably are the most advanced in amino acid starvation therapies and have reached clinical trials. This is the first example of the combined damaging of two cellular compartments, mitochondria and nucleus, by metabolic stress.

Glycolysis occurs in most organisms in the cytosol of the cell. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH). Here, we performed an unbiased assessment of whole-genome mRNA expression, histone methylation, and acetylation patterns after training human primary monocytes with b-glucan, and found mTOR and HIF-1a regulate glycolysis.

Firstly, as previous study reports that epigenetic reprogramming at the level of histone H3 methylation has been proposed as the molecular mechanism responsible for long-term memory of innate immunity. We take a transcriptome analysis to dissect which pathways are modulated in the mHIF-1a KO mice, and compared the differential RNA expression profiles of wild-type and mHIF-1a KO mice. Several interesting genes were specifically up-regulated in wild-type but not in mHIF-1a KO mice.

Hypoxia decreases the activity of the ETC complexes I and IV through HIF-1a. Our study introduces an interesting initial step in understanding the glycolytic process in trained immunity. These results show that stimulation of HIF-1a–mediated glycolysis in myeloid cells is crucial for mounting trained immunity in vivo.

The identification of glycolysis as a fundamental process in trained immunity further indicates a key regulatory role for metabolism in innate host defense and also defines a novel therapeutic target in both infectious and inflammatory diseases.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.