High-resolution respirometry Dotaz Zobrazit nápovědu
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used drugs for lowering blood lipid levels and preventing cardiovascular diseases. However, statins can have serious adverse effects, which may be related to development of mitochondrial dysfunctions. The aim of study was to demonstrate the in vivo effect of high and therapeutic doses of statins on mitochondrial respiration in blood platelets. Model approach was used in the study. Simvastatin was administered to rats at a high dose for 4 weeks. Humans were treated with therapeutic doses of rosuvastatin or atorvastatin for 6 weeks. Platelet mitochondrial respiration was measured using high-resolution respirometry. In rats, a significantly lower physiological respiratory rate was found in intact platelets of simvastatin-treated rats compared to controls. In humans, no significant changes in mitochondrial respiration were detected in intact platelets; however, decreased complex I-linked respiration was observed after statin treatment in permeabilized platelets. We propose that the small in vivo effect of statins on platelet energy metabolism can be attributed to drug effects on complex I of the electron transport system. Both intact and permeabilized platelets can be used as a readily available biological model to study changes in cellular energy metabolism in patients treated with statins.
OBJECTIVES: The bipolar affective disorder (BAD) pathophysiology is multifactorial and has not been fully clarified. METHOD: We measured selected mitochondrial parameters in peripheral blood components. The analyses were performed for patients suffering from a manic episode during remission and were compared to those performed for healthy controls. BAD was clinically evaluated using well-established diagnostic scales and questionnaires. Mitochondrial respiration was examined in intact and permeabilized blood platelets using high-resolution respirometry. The citrate synthase (CS) and electron transport system (ETS) complex (complex I, II, and IV) activities were examined in platelets. RESULTS: The CS, complex II and complex IV activities were decreased in the BAD patients, complex I activity was increased, and the ratio of complex I to CS was significantly increased. In the intact platelets, respiration after complex I inhibition and residual oxygen consumption were decreased in the BAD patients compared to the healthy controls. In the permeabilized platelets, a decreased ETS capacity was found in the BAD patients. No significant differences were found between BAD patients in mania and remission. CONCLUSION: Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. We conclude that complex I and its abnormal activity contribute to defects in cellular energy metabolism during a manic episode and that the deficiency in the complex's functioning, but not the availability of oxidative phosphorylation substrates, seems to be responsible for the decreased ETS capacity in BAD patients. The observed parameters can be further evaluated as 'trait' markers of BAD.
- MeSH
- bipolární porucha komplikace farmakoterapie metabolismus MeSH
- citrátsynthasa metabolismus MeSH
- dospělí MeSH
- elektronový transportní řetězec metabolismus MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- trombocytopatie komplikace metabolismus MeSH
- trombocyty metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Úvod: Příčiny vzniku bipolární afektivní poruchy (BAP) jsou multifaktoriální a nebyly dosud plně objasněny. Na patofyziologii BAP se mohou podílet také mitochondriální dysfunkce. Metoda: Měřili jsme vybrané mitochondriální parametry v trombocytech izolovaných z periferní krve u pacientů trpících manickou fází BAP, v jejich remisi a u zdravých kontrol. BAP byla klinicky hodnocena pomocí diagnostických škál a dotazníků. Aktivity citrátsyntázy (CS) a elektronového transportního systému (ETS) - komplexů I, II, a IV byly měřeny spektrofotometricky Mitochondriální respirace byla zkoumána v intaktních a permeabilizovaných trombocytech za použití respirometrie s vysokým rozlišením. Výsledky: Aktivity komplexů II, IV a CS byly u pacientů s BAP sníženy, aktivita komplexu I byla zvýšena, a poměr komplexu I k CS byl signifikantně zvýšen. V intaktních trombocytech byly respirace po inhibici komplexu I a reziduální spotřeba kyslíku sníženy u pacientů s BAP ve srovnání se zdravými kontrolami. V permeabilizovaných trombocytech byla prokázána snížená kapacita ETS u pacientů s BAP. Nebyly prokázány signifikantní rozdíly mezi pacienty s manickou fází BAP a pacienty v remisi. Závěr: Pokles kapacity ETS u pacientů s BAP lze vysvětlit nedostatečnou funkcí enzymů citrátového cyklu a enzymových komplexů systému oxidativní fosforylace. Zvýšení aktivity komplexu I by mohl představovat kompenzační mechanismus ke sníženým aktivitám CS a narušené funkci komplexů II a IV. Předpokládáme, že komplex I a změny v jeho aktivitě přispívají k eliminaci poruch buněčného energetického metabolismu při BAP způsobených nedostatečným fungováním komplexů II a IV. Sledované parametry by měly být dále zkoumány jako "trait" markery BAP.
Introduction: The reasons for bipolar affective disorder (BAD) development are multifactorial and have not been fully clarified. Mitochondrial dysfunctions can be implicated in pathophysiology of BAD. Method: We measured selected mitochondrial parameters in blood platelets isolated from peripheral blood. The analyses were performed for patients suffering from a manic episode during remission and were compared to those performed for healthy controls. BAD was clinically evaluated using well-established diagnostic scales and questionnaires. Activities of electron transport system (ETS) complexes - complex I, II, and IV and citrate synthase (CS) were examined spectrophotometrically Mitochondrial respiration was examined in intact and permeabilized blood platelets using high-resolution respirometry. Results: The CS, complex II and complex IV activities were decreased in the BAD patients, complex I activity was increased, and the ratio of complex I to CS was significantly increased. In the intact platelets, respiration after complex I inhibition and residual oxygen consumption were decreased in the BAD patients compared to the healthy controls. In the permeabilized platelets, a decreased ETS capacity was found in the BAD patients. No significant differences were found between BAD patients in mania and remission. Conclusion: Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. We conclude that complex I and its abnormal activity contribute to elimination of defects in cellular energy metabolism during a manic episode and that the deficiency in the complex's II and IV functioning. The availability of oxida-tive phosphorylation substrates, seems to be not responsible for the decreased ETS capacity in BAD patients. The observed parameters can be further evaluated as ´trait´ markers of BAD.
