FRUCTOSE PROTECTS HEPATOCYTES FROM HYPOXIA BY INHIBITION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION

William R. Irwin
Department of Biochemistry, University of South Dakota School of Medicine, Vermillion, SD

Fructose, but not glucose, exerts a protective effect on the viability of hepatocytes under conditions of hypoxia. The protective effect has been attributed to the ability of fructose to provide ATP via anaerobic glycolysis. We have found that D-glyceraldehyde (D-GA), a normal intermediate of fructose metabolism, as well as its L-isomer (L-GA), both protect liver cells from chemical hypoxia at least as well as fructose. However, neither fructose, D-GA nor L-GA significantly influences cellular ATP levels during hypoxia. Although L-GA and D-GA protect equally well, L-GA is a much poorer glycolytic substrate. This indicates that protection is not related to cellular ATP levels.

We have found that both D-GA and L-GA inhibit formation of the mitochondrial permeability transition (MPT) in isolated mitochondria under both chemical hypoxia or aerobic conditions (Ki = 0.2 mM). Protection of isolated mitochondria cannot be explained by glycolytic pathways. Under aerobic conditions this protective effect seems to be related to oxidation of these substrates by the mitochondrial aldehyde dehydrogenase (ALDH). Other ALDH substrates, such as erythrose, threose, propionaldehyde and butyraldehyde (but not acetaldehyde) are also protective. Inhibition of ALDH by chloral hydrate blocks the protective effect of the aldoses, but not the simple aldehydes. The mechanism by which D-GA and L-GA prevent formation of the MPT during chemical hypoxia is unclear, but is difficult to reconcile with ALDH activity. We propose that a substantial part of the protective effect of fructose under either aerobic or hypoxic conditions is via inhibition of the MPT by glyceraldehyde, and not by provision of glycolytic ATP.