Mitochondrial complex I dysfunction induced by cocaine and cocaine plus morphine in brain and liver mitochondria

Abstract

h i g h l i g h t s• Brain and liver mitochondrial respiration is differentially affected by the drugs.• Cocaine-induced inhibition of complex I is more evident in brain mitochondria.• Dependence on complex I may explain differences in brain and liver mitochondria.• The drug combination had a greater effect on brain state 3 than the drugs per se.• In other parameters the drug combination had similar effects to cocaine per se. a r t i c l e i n f o t r a c tMitochondrial function and energy metabolism are affected in brains of human cocaine abusers. Cocaine is known to induce mitochondrial dysfunction in cardiac and hepatic tissues, but its effects on brain bioenergetics are less documented. Furthermore, the combination of cocaine and opioids (speedball) was also shown to induce mitochondrial dysfunction. In this work, we compared the effects of cocaine and/or morphine on the bioenergetics of isolated brain and liver mitochondria, to understand their specific effects in each tissue. Upon energization with complex I substrates, cocaine decreased state-3 respiration in brain (but not in liver) mitochondria and decreased uncoupled respiration and mitochondrial potential in both tissues, through a direct effect on complex I. Morphine presented only slight effects on brain and liver mitochondria, and the combination cocaine+morphine had similar effects to cocaine alone, except for a greater decrease in state-3 respiration. Brain and liver mitochondrial respirations were differentially affected, and liver mitochondria were more prone to proton leak caused by the drugs or their combination. This was possibly related with a different dependence on complex I in mitochondrial populations from these tissues. In summary, cocaine and cocaine+morphine induce mitochondrial complex I dysfunction in isolated brain and liver mitochondria, with specific effects in each tissue.

Role of Mitochondria on the Neurological Effects of Cocaine

“…Cocaine also decreased FCCPstimulated respiration and ΔΨ m in complex I-energized brain and liver mitochondria, but not in mitochondria energized with complex II substrates, suggesting an important role of complex I in mediating cocaine effects in both tissues. A decrease in ΔΨ m also occurred in cocaine-exposed liver mitochondria energized through complex II, suggesting that, at least in the liver, cocaine effect on ΔΨ m is independent of mitochondrial respiration impairment (Cunha-Oliveira et al, 2013d), probably due to a dissipation of charge associated with the weak base effect, as described for other intracellular compartments (Sulzer & Rayport, 1990). Cocaine effect on complex I was shown to be independent of disrupted nicotinamide adenine nucleotide reduced form (NADH) supply, because the drug also decreased oxygen consumption in mitochondrial fractions energized with NADH.…”

“…Complex I seems to be a direct target of cocaine in rat brain mitochondria (Cunha-Oliveira et al, 2013d;Dietrich et al, 2004), and also in heart (Vergeade et al, 2010;Yuan & Acosta, 1996, 2000 and liver mitochondria (Cunha-Oliveira et al, 2013c;Devi & Chan, 1997). In vitro exposure to cocaine was shown to affect the respiratory chain in different manners in liver and brain FIGURE 21.2 Interactions of cocaine with mitochondrial functions.…”

“…Cocaine and Brain Mitochondria Chapter | 21 207 mitochondria, but both tissues shared an effect on complex I-mediated respiration (Cunha-Oliveira et al, 2013d). Cocaine decreased state-3 respiration in brain, but not liver, mitochondria energized with complex I substrates, indicating a tissue-specific interaction with the oxidative phosphorylation system (OXPHOS) under complex I energization.…”

“…Since cocaine can accumulate inside cellular compartments due to the weak base effect (Sulzer & Rayport, 1990), it can reach high concentrations inside mitochondria and produce direct effects on mitochondrial function, such as the disruption of mitochondrial transmembrane electric potential (ΔΨ m ) (Cunha-Oliveira et al, 2006a, 2013d.…”

“…Cocaine effect on complex I was shown to be independent of disrupted nicotinamide adenine nucleotide reduced form (NADH) supply, because the drug also decreased oxygen consumption in mitochondrial fractions energized with NADH. The possibility of a dysfunction on other components of the respiratory chain was discarded since cocaine did not affect succinate-mediated oxygen consumption in the same mitochondrial fractions (Cunha-Oliveira et al, 2013d). These data suggest a direct effect of cocaine on complex I activity, although the complete mechanism still needs to be elucidated.…”