MPP(+)-induced neurotoxicity in mouse is age-dependent: evidenced by the selective inhibition of complexes of electron transport.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has been demonstrated to cause selective neurotoxicity by inhibiting complex I in mitochondria, through its toxic metabolite 1-methyl-4-phenylpyridine (MPP+) which is formed during the bioactivation of MPTP by monoamine oxidase B. In this report, we have evaluated the effect of MPP+ on the 4 mitochondrial respiratory chain complexes by incubating brain mitochondria of mice at 3 different age groups with MPP+ (200 microM) and monitoring enzyme activities of complexes I, II, III, and IV at 5, 10, 15, 30, 60, and 120 min. Complexes I, III, and IV showed significant inhibition within 15 min in all the age groups studied, followed by some recovery in enzyme activities upon further incubation for complexes I and IV. However, complex II was not affected by MPP+ at any age. Our data suggest that inhibition of complexes I, III, and IV by MPP+ efficiently restrict the transport of electrons down the respiratory chain which ultimately leads to decreased ATP production. This could further aggravate oxidative stress as ATP is required for the synthesis of glutathione (GSH), one of the important scavengers of free radicals. In this study, inhibition was more severe in mitochondrial preparations from older rather than younger mice. Additionally, young animals showed faster recovery following inhibition than old animals for complex I. Impaired respiratory chain function in older animals compared to younger ones supports the hypothesis of accumulation of age-related mitochondrial DNA mutations which partly encode for subunits of complexes I, III, and IV. From this study, it seems that inhibition of complexes I, III, and IV may be the underlying cause of neurotoxicity due to MPP+ which could be intensified by age-associated dysfunction of electron transport.
Desai
V G
VG
Division of Genetic Toxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079-9502, USA.
Feuers
R J
RJ
Hart
R W
RW
Ali
S F
SF
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D015259:Dopamine Agents / Q000633:toxicity*; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D003576:Electron Transport Complex IV / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology
D015259:Dopamine Agents; D016660:NAD(P)H Dehydrogenase (Quinone); D003576:Electron Transport Complex IV; D015655:1-Methyl-4-phenylpyridinium