Interactions Of Mitochondria-Targeted Drugs And Poisons With Mitochondria And Serum Albumin

Mitochondrion, whose main function is ATP synthesis, has long been recognized as the power source of the cell. Apart from this important function, it is now widely accepted that several mitochondrial events control the apoptosis process.Because of their functions in energy production and in regulation of cell death, mitochondria have been considered to be a potentially important target for anti-cancer drug development. Anticancer drugs that directly target mitochondria have the potential to provide new opportunities for therapeutic intervention in cancer. Over the years, Effects of these compounds on mitochondrial function and metabolic homeostasis have been examined in various in vitro and in vivo models using various experimental systems, but the molecular and cellular mechanisms responsible for the anti-neoplastic effects have not been fully elucidated.Mitochondrial permeability transition (MPT) is now considered to be a critical event in the induction of the apoptotic process, but unfortunately, many questions regarding the mitochondria-mediated cell-death pathways remain unanswered. Our investigations are aimed at getting further information on the effects of these compounds on mitochondria, especially on MPT process. We wish to provide a comprehensive understanding of the effects of these compounds on MPT and shed new light on the mechanism of mitochondrial apoptosis. Furthermore, the transportation, distribution and metabolism of mitochondrial targeted compounds in body are of great importance in pharmacy, pharmacology and biochemistry, and is hoped to afford valuable information about clinic therapy.This thesis consists of five chapters:Chapter 1:This chapter summarized the current understanding of mitochondrial-targeted compounds that show the greatest promise for the treatment of human malignancies. Moreover, the perspectives and future developments of this area of research have been discussed.Chapter 2:We analyzed the effects of two anti-cancer drugs gossypol and resveratrol on mitochondrial function and structure. These compounds induced swelling, loss of membrane potential and changes of membrane fluidity thus suggesting an apparent higher potential for MPT. The respiration of mitochondria was also affected. Our data also confirm that mitochondria are the target inducing apoptosis of tumor cells. Interactions between mitochondrial respiration function and six synthetical phenyl dichloroacetamide derivatives were compared.Chapter 3:By using microcalorimetry, we studied the effect of DNP on the metabolism of mitochondria. Results show that DNP can stimulate mitochondria metabolism, and the power-time curve is different from that ADP added. We investigated the effects of nicotine on mitochondria. The present study shows that nicotine inhibited Ca2+-induced MPT and affected the respiratory chain. This may explain a part of the beneficial and protective effects of nicotine in few neurodegenerative diseases and toxicity in other cases. Effects of three vanadium compounds on mitochondria were compared.Chapter 4:Overviews of deleterious action of Cd2+ and Cu2+ on rat liver mitochondria were investigated using spectroscopic and microscopic methods. All these observations on different concentrations of Cd2+ were inferred to the mechanism that Cd2+ can directly affect MPT on two separate localization sites:classic Ca2+ triggering site and thiol (-SH) groups of membrane proteins matched by MPT Pore opening (defined as "S" site), respectively. Under high concentrations of Cd2+, other free -SH groups in mitochondrial matrix may be involved in this process. Cu2+ induced changes of mitochondrial membrane fluidity and collapse of membrane potential. The treatments of HSA, DTT, EGTA and CsA can inhibit the process. It was proposed that Cu2+ induced MPT and it was highly possible that thiol groups and Ca2+ triggering site were involved in the mechanism.Chapter 5:The binding interactions of mitochondrial-targeted compounds with serum albumin (HSA or BSA) were investigated by various spectroscopic techniques under simulative physiological conditions. The fluorescence quenching constants (Ksv), thermodynamic parameters AH and AS were calculated. Isothermal titration calorimeter (ITC) method and theoretical molecular modeling method were also used to afford some information. The effects of ligands on the conformation of serum albumin have been analyzed by means of three dimensional fluorescence spectra, synchronous fluorescence spectra and CD spectra.