Function and expression study uncovered hepatocyte plasma membrane ecto-ATP synthase as a novel player in liver regeneration.

ATP synthase, canonically mitochondrial-located, is reported to be ectopically expressed on the plasma membrane outer face of several cell types. We analysed, for the first time, the expression and catalytic activities of the ecto- and mitochondrial ATP synthase during liver regeneration. Liver regeneration was induced in rats by two-third partial hepatectomy. The protein level and the ATP synthase and/or hydrolase activities of the hepatocyte ecto- and mitochondrial ATP synthase were analysed on freshly-isolated hepatocytes and mitochondria from control, sham-operated and partial-hepatectomised rats. During the priming phase of liver regeneration, 3h after partial-hepatectomy, liver mitochondria showed a marked lowering of the ATP synthase protein level that was reflected in the impairment of both ATP synthesis and hydrolysis. Ecto-ATP synthase level, in 3h partial-hepatectomy hepatocytes, was decremented as the mitochondrial one, associated with a lowering of the ecto-ATP hydrolase activity coupled to proton influx. Noteworthy, the ecto-ATP synthase activity coupled to proton efflux was completely inhibited in 3h partial-hepatectomy hepatocytes, even in the presence of a marked intracellular acidification that would sustain it as in control and sham-operated ones. At the end of the liver regeneration, 7 days after partial-hepatectomy, the level and the catalytic activities of the ecto- and mitochondrial ATP synthase reached the control and sham-operated values. The specific modulation of hepatocyte ecto-ATP synthase catalytic activities during liver regeneration priming phase may modulate the extracellular ADP/ ATP levels and/or proton influx/efflux trafficking, candidating hepatocyte ecto-ATP synthase as a novel player in the liver regeneration process.