Understanding the molecular interactions of Fe-S cluster proteins in liver regeneration

Liver-related diseases sometimes requiring transplant or not, continue to present a major burden to global health. Mitochondrial dynamics is central to the cellular bioenergetics of liver regeneration, a major aspect of liver transplantation. Iron-Sulphur (Fe-S) cluster biogenesis, as an essentiality of mitochondrial (biogenesis) dynamics, may be involved in regulation of several diverse cellular processes, key to hepatocellular proliferation. Fe-S cluster-containing genes such as (mitoNEET, MINER1, IRP1, ACO2, SDH, GLRX5) are known to play critical cellular functions. However, molecular basis of the cellular functions of Fe-S proteins and their interactions with partner genes (PGC-1α, MFRN, HIF-2α and c-MYC) remain to be explored in the context of liver regeneration. After a 70% partial hepatectomy, some selected genes of interest were examined for their gene and protein activity using RT-PCR and Western Blotting assays. Succinate receptor activity and hepatocyte proliferation rates were determined with ELISA and PCNA immunohistochemistry tests respectively. In our study, gene activities of mitoNEET, IRP1, MINER1 and SDHA as Fe-S genes and partner genes: mitoferrin, HIF-2α and c-MYC, were found significantly expressed (p≤0.05) in the PH groups, except for mitoferrin. Significant mRNA expressions (p≤0.05) of DMT-1, mitoNEET, IRP1 and HIF-2α, was also seen in the PH groups. PGC-1α and MINER1 were also significantly expressed intra-PH (p≤0.05). Expressional patterns of Fe-S gene relative to their molecular interactions with partner genes, seem to define their cellular functions. Such a gene interaction network of molecular interactions involving Fe-S genes with partner genes, may promote hepatocyte proliferation via metabolic rewiring of cellular bioenergetics via regulation of iron, oxygen and ROS metabolism coupled to the major molecular events of hepatocyte hypertrophy-hyperplasia dynamics in the early-intermediate phases of liver regeneration. Fe-S protein biogenesis and degradation is delicately balanced to guide the molecular basis of their cellular function.