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  • The two isoforms LDH A and


    The two isoforms LDH-A and LDH-B catalyze the same reaction, conversion of pyruvate to lactate at the end of glycolysis. LDH-A is expressed in the liver. Humans with a hereditary deficiency of the A or B LDH isoforms are free of symptoms, except for muscle rigidity and myoglobinuria following strenuous exercise.[28], [29] Therefore, inhibition of LDH-A by galloflavin is not expected to be toxic. Interestingly, we found that besides LDH inhibition, galloflavin also inhibits PDHC. In resazurin synthesis to inherited LDH deficiency, PDHC deficiency resazurin synthesis is responsible for a severe disease in humans. Nevertheless, inhibition of PDHC by galloflavin does not appear to be complete, although it was sufficient to prevent the increase in activity induced by CD95-Ab. Moreover, toxicity data suggest that galloflavin has good tolerability and doses up to 400 mg/kg injected i.p. that are five times higher than the maximum dose used in this study, did not result in lethal effects in mice. The mechanism underlying nuclear translocation of metabolic enzymes remains largely unknown. Protein trafficking can be regulated by various proteins that bind and mediate translocation. PDHC translocation appears to involve Hsp70 because its inhibition decreases nuclear PDHC levels. However, mitochondria-derived vesicles (MDVs) have also been suggested as a mechanism of organelle communication within the cell. MDVs allow trafficking of mitochondrial proteins to lysosomes. However, whether they can transfer proteins to the nucleus has not been shown yet. Defining the mechanisms involved in metabolic enzyme nuclear translocation may lead to the development of specific translocation inhibitors with potential applications in acute liver failure. Acute liver failure is characterized by a sudden and massive death of liver cells. The injured hepatocyte may itself aggravate and exacerbate liver injury by immune activation, often leading to a systemic inflammatory response syndrome that is the most common cause of death. Fas and TNF-α receptor activation are well-characterized processes leading to secretion of TNF-α that aggravates apoptosis, and increased hepatic chemokines that recruit TNF-α-secreting neutrophils to the liver. Regardless of various etiologies, clinical evidence suggests that acute liver failure is generally associated with significant and uncontrolled activation of systemic inflammation, which may consequently lead to multiple organ failure and poor prognosis.[26], [35] In this study, we found that the pharmacological inhibition of LDH and PDHC by galloflavin reduced liver damage and apoptosis, decreased hepatic cytokine expression and improved survival. Treatment of acute liver failure is currently based only on supportive measurements and there are no drugs that can change the natural history of the disease. Prior to transplantation most studies reported less than 15% survival in acute liver failure. In the Western world, liver transplantation has improved the chance of survival in patients with acute liver failure. Nevertheless, 20 to 50% of patients listed for liver transplantation die before an organ becomes available as a result of irreversible cerebral edema or sepsis with multi-organ failure. In contrast, in developing countries the mortality for acute liver failure remains extremely high. Our results imply that treatment with galloflavin increases resistance to acute liver injury and therefore, it could prolong the time until transplantation or even allow the endogenous regenerative capacity of the liver to rescue the organ. In conclusion, the results of this study suggest that nLDH and/or nPDHC are targets for therapy of patients with acute liver failure of different etiologies.
    Financial support This work was supported by the European Research Council (IEMTx) and Fondazione Telethon Italy (TCBP37TELC and TCBMT3TELD) to N.B.-P.
    Conflict of interest Please refer to the accompanying ICMJE disclosure forms for further details.