An adenosine derivative promotes mitochondrial supercomplexes reorganization and restoration of mitochondria structure and bioenergetics in a DEN-induced hepatocellular carcinoma model

Hepatocellular carcinoma (HCC) has become highly relevant in oncology research because of its high mortality rate and difficult diagnosis and treatment. Most chronic liver diseases, including HCC, are characterized by bioenergetics impairment associated with dysfunctional mitochondria. However, no data are available about the relationship between mitochondrial supercomplexes formation and ATP production rates in HCC. Our group has developed an adenosine derivative, IFC-305, which improves mitochondrial function, and it has been proposed as a therapeutic candidate for liver diseases, including HCC. Therefore, we aimed to determine the role of IFC-305 on both mitochondrial structure and bioenergetics in a sequential cirrhosis-HCC model. Our results showed that IFC-305 administration in DEN-induced HCC in rats decreased the number and size of liver tumors, reduced the expression of tumoral markers from hepatic tissue and AFP serum levels, and reestablished the typical architecture of the liver parenchyma. Additionally, the livers of treated rats showed a reduction of mitochondria number, recovery of the mtDNA/nDNA ratio, and mitochondrial length compared to untreated HCC condition. Also, IFC-305 increased cardiolipin and phosphatidylcholine levels and promoted the reorganization of high molecular weight mitochondrial supercomplexes (hmwSC) (V 2 , I + III 2  + IV, I + III 2  + IV 2 , and I + III 2  + IV 3 ). Furthermore, the expression levels of hmwSC assembly-related genes were correlated with changes in the mitochondrial structure. Additionally, administration of IFC-305 in HCC modified the expression of several genes encoding elements of complexes I, II, III, IV, and V and increased the ATP levels by recovering the complex I, III, and V activity. We propose that IFC-305 restores the mitochondrial bioenergetics in HCC by normalizing the quantity, morphology, and function of mitochondria, possibly as part of its hepatoprotective mechanism of action.