Mitochondria generate cellular energy through TCA
cycle and electron transport chain. ETC is located in the inner mitochondrial
membrane. The products of TCA cycle ie the reducing equivalents (NADH and FADH2)
are reoxidized via the transfer of electrons through the electron transport
chain (ETC). NADH donates electrons to
complex I (NADH-ubiquinone oxidoreductase)) of the ETC and FADH2 to complex II ( succinate-ubiquinone
oxidoreductase ). Complex
I and II then transfer the electrons to ubiquinone Ubiquinone passes its
electrons to complex III (Ubiquinol-cytochrome c oxidoreductase), cytochrome C, complex IV (Cytochrome c oxidase), and finally to molecular oxygen. As the electrons
are transferred through the ETC the energy is used to shuttle protons across
the membrane. This creates a voltage across the inner and outer membrane of the
mitochondria and drives ATP synthesis. Translocation of
protons across the mitochondrial inner membrane, thereby creating the
transmembrane electrochemical gradient (150–200 mV negative to the cytosol). The
electrochemical potential make ATP from ADP and Pi, mediated by
proton movement back through the ATP synthase complex. Under normal conditions,
the proton gradient is also diminished by H+ ‘leak’ to the matrix.
The ‘leak’ occurs either via non-protein membrane pores, protein–lipid
interfaces (H+ leak), or by proton channels known as uncoupling
proteins (UCPs). In hyperglycemic conditions,
the number of substrates entering the TCA cycle is greatly increased and consequently
the number of reducing equivalents donating electrons to the ETC is also increased.
Once the ETC reaches a threshold voltage across the membrane the electrons begin
to back up at complex III. These electrons are then donated to molecular
oxygen, which in turn results in an increase in mitochondrial superoxide
production (Brownlee, 2001). The
mitochondrial isoform of superoxide dismutase degrades oxygen free radical to
hydrogen peroxide, which is later converted to H2O and O2 by other enzymes.Thus
mitochondria initiates hyperglycemia-induced superoxide production, this, in
turn, can activate a number of other superoxide production pathways which may
amplify the original damaging effect of hyperglycemia (Ferdinando and Michael, 2010). These pathways include redox changes, NADPH oxidases, and
uncoupled eNOS .

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