Effects of neurofilamentous axonopathy-producing neurotoxicants on in vitro production of ATP by brain mitochondria.
The site and mode of action of acrylamide (ACR), gamma-diketone hexacarbons and 3',3'-iminodipropionitrile (IDPN) in producing a neurofilamentous axonopathy are unknown. Whether the neuropathy is caused by reduction in axonal transport produced by energy depletion is under investigation. Reductions in the quantity of proteins fast transported following a single dose of ACR or neurotoxic gamma-diketones have been reported. The current study examines the in vitro effects of these toxicants upon ATP production by mitochondria. Isolated rat brain mitochondria incubated for 30 min at 37 degree C with neurotoxic doses of ACR (0.7 mM) or 3,4-dimethyl-2,5-hexanedione (0.25 mM) retained similar capacities for synthesis of ATP from pyruvate and endogenous concentrations of ATP compared to controls. 2,5-Hexanedione (2,5-HD; 4 mM) and IDPN (0.1%) significantly reduced the rate of synthesis (-22.5% and -15%, respectively); but only 2,5-HD decreased the endogenous concentration of ATP (-21.6%) following a single 30 min exposure. Toxicant action on ATP production is limited to 2,5-HD; the correlation between the toxicant-induced changes in axonal transport and mitochondrial ATP production demonstrate the necessity to evaluate other structures as the critical site of action in producing axonal transport changes.
Sickles
D W
DW
Department of Anatomy, Medical College of Georgia, Augusta 30912.
Fowler
S R
SR
Testino
A R
AR
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000648:ultrastructure*; D001921:Brain / Q000201:enzymology*; D007382:Intermediate Filaments / Q000473:pathology; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains
D009498:Neurotoxins; D000255:Adenosine Triphosphate