Effect of sydnone SYD-1, a mesoionic compound, on energy-linked functions of rat liver mitochondria.
An important antitumour effect of SYD-1 (3-[4-chloro-3-nitrophenyl]-1,2,3-oxadiazolium-5-olate) has been shown. We now report the effects of this mesoionic compound on mitochondrial metabolism. SYD-1 (1.5 micromol mg(-1) protein) dose-dependently inhibited the respiratory rate by 65% and 40% in state 3 using sodium glutamate and succinate, respectively, as substrates. Phosphorylation efficiency was depressed by SYD-1, as evidenced by stimulation of the state 4 respiratory rate, which was more accentuated with glutamate ( approximately 180%) than with succinate ( approximately 40%), with 1.5 micromol mg(-1) protein of SYD-1. As a consequence of the effects on states 3 and 4, the RCC and ADP/O ratios were lowered by SYD-1 using both substrates, although this effect was stronger with glutamate. The formation of membrane electrical potential was inhibited by approximately 50% (1.5 micromol SYD-1mg(-1) protein). SYD-1 interfered with the permeability of the inner mitochondrial membrane, as demonstrated by assays of mitochondrial swelling in the presence of sodium acetate and valinomycin +K(+). SYD-1 (1.5 micromol mg(-1) protein) inhibited glutamate completely and succinate energized-mitochondrial swelling by 80% in preparations containing sodium acetate. The swelling of de-energized mitochondria induced by K(+) and valinomycin was inhibited by 20% at all concentrations of SYD-1. An analysis of the segments of the respiratory chain suggested that the SYD-1 inhibition site goes beyond the complex I and includes complexes III and IV. Glutamate dehydrogenase was inhibited by 20% with SYD-1 (1.5 micromol mg(-1) protein). The hydrolytic activity of complex F(1)F(o) ATPase in intact mitochondria was greatly increased ( approximately 450%) in the presence of SYD-1. Our results show that SYD-1 depresses the efficiency of electron transport and oxidative phosphorylation, suggesting that these effects may be involved in its antitumoural effect.
Halila
Gerusa Clazer
GC
Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
de Oliveira
Maria Benigna Martinelli
MB
Echevarria
Aurea
A
Belém
Alice Carneiro
AC
Rocha
Maria Eliane Merlin
ME
Carnieri
Eva Gunilla Skare
EG
Martinez
Glaucia Regina
GR
Noleto
Guilhermina Rodrigues
GR
Cadena
Silvia Maria Suter Correia
SM
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D007477:Ions / Q000737:chemistry; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D008933:Mitochondrial Swelling / Q000187:drug effects; D015394:Molecular Structure; D009840:Oligomycins / Q000494:pharmacology; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013558:Sydnones / Q000737:chemistry / Q000494:pharmacology*
C524256:3-(4-chloro-3-nitrolphenyl)-1,2,3-oxadiazolium-5-olate; D007477:Ions; D009840:Oligomycins; D010069:Oxadiazoles; D013558:Sydnones; D000251:Adenosine Triphosphatases