Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson's disease

Abstract

The study has demonstrated that dopamine induces membrane depolarization and a loss of phosphorylation capacity in dose-dependent manner in isolated rat brain mitochondria during extended in vitro incubation and the phenomena are not prevented by oxyradical scavengers or metal chelators. Dopamine effects on brain mitochondria are, however, markedly prevented by reduced glutathione and N-acetyl cysteine and promoted by tyrosinase present in the incubation medium. The results imply that quinone oxidation products of dopamine are involved in mitochondrial damage under this condition. When PC12 cells are exposed to dopamine in varying concentrations (100-400μM) for up to 24h, a pronounced impairment of mitochondrial bio-energetic functions at several levels is observed along with a significant (nearly 40%) loss of cell viability with features of apoptotic nuclear changes and increased activities of caspase 3 and caspase 9 and all these effects of dopamine are remarkably prevented by N-acetyl cysteine. N-acetyl cysteine also blocks nearly completely the dopamine induced increase in reactive oxygen species production and the formation of quinoprotein adducts in mitochondrial fraction within PC12 cells and also the accumulation of quinone products in the culture medium. Clorgyline, an inhibitor of MAO-A, markedly decreases the formation of reactive oxygen species in PC12 cells upon dopamine exposure but has only mild protective actions against quinoprotein adduct formation, mitochondrial dysfunctions, cell death and caspase activation induced by dopamine. The results have indicated that quinone oxidation products and not reactive oxygen species are primarily involved in cytotoxic effects of dopamine and the mitochondrial impairment plays a central role in the latter process. The data have clear implications in the pathogenesis of Parkinson's disease.

Bioactive l-DOPA induced quinoprotein formation to inhibit root growth of cucumber seedlings

“…Production of quinoproteins may inhibit plant growth through cross linking of membrane proteins, deactivation of enzymes, mitochondrial dysfunction, disrupting homeostasis and DNA fragmentation leading to apoptosis. [12][13][14]23) Previously, it has been reported that l-DOPA inhibited mitochondrial complex I (NADH dehydrogenase) and complex IV (cytochrome c oxidase) activities in rat and human mitochondria, respectively. 24,25) Moreover, quinoproteins from dopaminequinone induced mitochondrial swelling and permeability transition of the mitochondrial membrane and reduced complex I activity and electron transport leading to dysfunction of mitochondria in human and rat brains.…”

“…24,25) Moreover, quinoproteins from dopaminequinone induced mitochondrial swelling and permeability transition of the mitochondrial membrane and reduced complex I activity and electron transport leading to dysfunction of mitochondria in human and rat brains. 12,26,27) Recent proteomics studies using radiolabeled dopamine showed that dopaminequinone covalently modified critical proteins such as mitochondrial chaperonin, ubiquinol-cytochrome c reductase, mortalin, mitofilin, creatine kinase, and NADH dehydrogenase in animal and human cells. 28,29) The covalent modification of these proteins by dopaminequinone may contribute to cytotoxicity.…”

“…11) Quinoprotein formation may inhibit the normal functioning of cells through mitochondrial swelling and dysfunction, deactivation of enzymes, disrupting homeostasis, covalent modification of critical proteins and damage to DNA leading to apoptosis. [12][13][14] Previous in vitro studies have shown that dopaquinone and dopaminequinone, oxidation products of l-DOPA, may bind covalently with cysteine to produce quinoproteins. 7) Furthermore, dopamine, which is a metabolite of l-DOPA, increased quinoproteins in animal and human cells causing cytotoxicity.…”

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

“…A number of studies performed with chemical stressors showed evidence of temporal, response and dose concordance were conducted in vitro, the temporal concordance is difficult to establish; however, can be expected based on the well know temporal sequence of the two KEs. (Swedlow et al, 1996;Jha et al, 2000;Chinta et al, 2006;Marella et al, 2008;Hajieva et al, 2009;Du et al, 2010;Jana et al, 2011;Choi et al, 2014;Park et al, 2014) KE3 => KE4 PPPs, Parkinson's disease and childhood leukaemia The experimental support linking the degeneration of DA neurons of nigrostriatal pathways with the manifestation of motor symptoms of PD comes from human in vivo observations as well as from monkey, mice and rat in vivo models exposed to an experimental toxin i.e. rotenone and MPTP.…”

“…DA-dependent PC12 cell death, decline in the transmembrane potential and in intracellular ATP, and decline in complex II/III activities were observed and were all completely prevented by the presence of NAC. (Jana et al, 2011).…”