Inhibition of the mitochondrial permeability transition by aldehydes.
Fructose has been shown to protect hepatocyte viability during hypoxia or exposure to mitochondrial electron transport inhibitors. We report here that the fructose metabolite D-glyceraldehyde (D-GA) is a good inhibitor of the mitochondrial permeability transition pore (PTP) in isolated rat liver mitochondria. We propose that a substantial portion of the protective effect of fructose on hepatocytes is due to D-GA inhibition of the permeability transition. Aldehydes which are substrates of the mitochondrial aldehyde dehydrogenase (mALDH) afford protection, while poor substrates do not. Protection is prevented by the ALDH inhibitor chloral hydrate. We propose that the NADH/NAD(+) ratio is the key to protection. The aldehydes phenylglyoxal (PGO) and 4-hydroxynonenal (4-HNE), which have previously been shown to inhibit the PTP, apparently function by a different mechanism independent of mALDH activity. Both PGO or 4-HNE are themselves potent inhibitors of ALDH, and their protective effect cannot be blocked by an ALDH inhibitor.
Irwin
William A
WA
Biochemistry and Molecular Biology Group, University of South Dakota School of Medicine, Vermillion, South Dakota 57069, USA.
Gaspers
Lawrence D
LD
Thomas
John A
JA
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D002122:Calcium Chloride / Q000037:antagonists & inhibitors; D005985:Glyceraldehyde / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability / Q000187:drug effects; D010658:Phenylglyoxal / Q000494:pharmacology; D051381:Rats
D000447:Aldehydes; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D005985:Glyceraldehyde; D000444:Aldehyde Dehydrogenase; C027576:4-hydroxy-2-nonenal; D002122:Calcium Chloride; D010658:Phenylglyoxal