The Mitochondrial Citrate Carrier SLC25A1/CIC and the Fundamental Role of Citrate in Cancer, Inflammation and Beyond

Abstract

The mitochondrial citrate/isocitrate carrier, CIC, has been shown to play an important role in a growing list of human diseases. CIC belongs to a large family of nuclear-encoded mitochondrial transporters that serve the fundamental function of allowing the transit of ions and metabolites through the impermeable mitochondrial membrane. Citrate is central to mitochondrial metabolism and respiration and plays fundamental activities in the cytosol, serving as a metabolic substrate, an allosteric enzymatic regulator and, as the source of Acetyl-Coenzyme A, also as an epigenetic modifier. In this review, we highlight the complexity of the mechanisms of action of this transporter, describing its involvement in human diseases and the therapeutic opportunities for targeting its activity in several pathological conditions.

Lipogenesis inhibitors: therapeutic opportunities and challenges

“…Cancer. As CIC expression is increased in several different cancer cells 130 and inhibition of CIC blunts cell growth 131 , CIC has emerged as an attractive target for anticancer drug development. All three CIC inhibitors have been found to exert anticancer activity in cultured cancer cell lines 123,132,133 and reduce tumour growth in vivo 132,133 .…”

A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret” of Cancer

“…Numerous studies have proven the proinflammatory and prooncogenic effects of CIC, as well as its participation in reversing the Warburg effect. The fundamental role of CIC and its upregulation in cancer, inflammation, and beyond is well described in a recent review article by Mosaoa et al [ 187 ]. CIC was found to be overexpressed in different types of cancer: breast cancer [ 188 ], colorectal cancer [ 189 ], prostate cancer [ 190 ], hepatomas [ 191 ], thyroid carcinoma [ 192 ], and others.…”

“…CIC is thought to support the cell proliferation by promoting OXPHOS and suppressing glycolysis, presumably due to the negative feedback loop that cytosolic citrate (provided by CIC) has on PFK1 [ 193 , 194 ] ( Figure 3(b) ). How CIC affects OXPHOS is not yet entirely clear, but such regulation may occur at least in part due to the promotion of malate entry into mitochondria, which in turn leads to increased flux in the Krebs cycle and the generation of reducing equivalents (such as NADH) for ETC [ 187 ].…”

Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

“…Many efforts have functionally characterized the MCF members [ 144 ] but little has been done to find specific and powerful inhibitors of the mitochondrial transporters [ 145 ]. The availability of such compounds may help fight cancer by specifically inhibiting mitochondrial metabolism as demonstrated solely for the mitochondrial citrate carrier [ 146 , 147 ]. An alternative strategy may be to use shRNAs or miRNAs to drastically decrease their expression levels [ 145 ].…”