In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

The mitochondrial CIC (citrate carrier) catalyses the efflux of citrate from the mitochondrial matrix in exchange for cytosolic malate. In the present paper we show that CIC mRNA and protein markedly increase in lipopolysaccharide-activated immune cells. Moreover, CIC gene silencing and CIC activity inhibition significantly reduce production of NO, reactive oxygen species and prostaglandins. These results demonstrate for the first time that CIC has a critical role in inflammation.

Citrate is an important substrate in cellular energy metabolism. It is produced in the mitochondria and used in the Krebs cycle or released into cytoplasm through a specific mitochondrial carrier, CIC. In the cytosol, citrate and its derivatives, acetyl-CoA and oxaloacetate, are used in normal and pathological processes. Beyond the classical role as metabolic regulator, recent studies have highlighted that citrate is involved in inflammation, cancer, insulin secretion, histone acetylation, neurological disorders, and non-alcoholic fatty liver disease. Monitoring changes in the citrate levels could therefore potentially be used as diagnostic tool. This review highlights these new aspects of citrate functions.