Mitochondria considered the power generator of the cell converting nutrients (carbohydrates, amino acids and fatty acids) into usable energy (ATP).


STRUCTURE
Mitochondria are bounded by a smooth outer and a highly folded inner membrane with embedded enzymes responsible for electron-transfer and ATP synthesis. The double membranes divide the mitochondria into two distinct parts: the acidic intermembrane space and the mitochondrial matrix containing DNA and the enzymes of the Krebs cycle.

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OXIDATIVE PHOSPHORYLATION
During glycolysis, glucose is broken down into pyruvate. Pyruvate is carried into the mitochondria and converted into Acetyl-CoA which enters the Kreb's cycle. During the oxidative cycle carbon dioxide is released and the hydrogen ions (protons) are picked up by nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD+) and transported to the respiratory chain.


Figure 2. Mitochondrial respiratory chain.Electron transfer through Complexes I, III, and IV of the inner membrane generates a proton gradient that is used to generate ATP through ATP synthase (Complex V).

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MITOCHONDRIAL PERMEABILITY TRANSITION (MPT) AND CELL DEATH
In the 1970s a reversible phenomenon was described by which mitochondria become freely permeable to low MW solutes. The transition causes mitochondrial depolarization, uncoupling and inhibition of oxidative phosphorylation with stimulation of mitochondrial ROS generation, mitochondrial swelling, and release of intramitochondrial solutes into the cytosol with molecular masses less than 1500 daltons such as cytochrome-c, second mitochondria-derived activator of caspases (smac)/direct IAP-binding protein with low pI (Diablo), and apoptosis inducing factor (AIF). AIF translocates to the nucleus, induces DNA loss, peripheral chromatin condensation, and digestion of chromatin into 50 kb fragments.
In the 1980s with the finding that immunosuppressive cyclosporin A specifically blocks transition start the identification of the proteins mediates the MPT. Another inhibitor of MPT, bongkrekic acid (BKA), prevents a number of phenomena linked to apoptosis in vitro. BKA is a specific ligand of the adenosine nucleotide translocator.


Figure 3. Model of the permeability transition pore complex. The MPT pore complexes comprises proteins from cytosol (hexokinase, HK), outer mitochondrial membrane (peripheral benzodiazepin receptor, PBR, voltage-dependent anion channel, VDAC), intermembrane space (creatine kinase, CK), inner membrane (adenosine nucleotide translocator, ANT) and matrix (cyclophilin D, CD). Additional proteins (Bcl-2, Bax) may participate in complex regulation. ANT conformations, influenced by endogenous (ADP, ATP) and exogenous (atractyloside, bongkrekic acid) ligands. Cyclophylin D interaction with inner membrane proteins is inhibited by cyclosporine A (CsA). Pore opening is facilitated by oxidation of vicinal thiols at the matrix site.





Figure 4. Model of mitochondria- dependent cell death. Under stress conditions cytochrome-c, procaspase-9, apoptotic protease acivating factor 1 (Apaf-1), apoptosis inducing factor (AIF) and second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI (smac/DIABLO) release into the cytosol and cause apoptosis by activation of caspase-3. Latter activates caspase-dependent DNas (CAD) causing DNA fragmentation and cleavage of poly-(ADP-ribose) polymerase (PARP). Heat shock proteins (HSP) can interfere with the cell death pathways by inhibiting the formation of apoptotic complexes.

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