Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 201

, 17 glycogen synthase kinase GSK3, glyceraldehyde 3-phosphate
dehydrogenase, and hexokinase, among others), phosphatases, and other signaling
proteins; 18 (3) post-translational modifications of mitochondrial proteins, such
as phosphorylation, S-nitrosylation, 19

(e.g., PKB, PKC

N acetylglucosamine
glycosylation, glutathiolation, sumoylation, and ubiquitination; and (4) inhibition
of the mitochondrial permeability transition pore.
The mitochondrial permeability transition pore comprises outer membrane
voltage-dependent anion channel, inner membrane, regulatory adenine nucleotide
transporter, and matrix cyclophilin-D, in addition to mitochondrial phosphate
carrier.
Under hypoxia, mitochondria generate toxic reactive oxygen species. The elec-
tron transport chain is the main ROS source. Nevertheless, cardiomyocytes sub-
jected to hypoxia keep mitochondrial activity under control, as they are equipped
with oxygen sensors prolyl hydroxylases and hypoxia-inducible factors [ 353 ].
During hypoxia, increased glycolysis causes a lactic acid accumulation, hence
intracellular pH reduction. Consequently, Na + -H + antiporter is activated and raises
intracellular Na + concentration that cannot be corrected by Na + -K + ATPase due to
the decline in ATP concentration. Increased intracellular Na + concentration leads to
elevated intracellular Ca 2 + concentration because Na + -Ca 2 + exchanger is inhibited
or reversed [ 353 ].
Reactive oxygen species are formed at complex-I and -III of the electron
transport chain and mainly via xanthine oxidase on xanthine formed by adenosine
degradation. Reactive oxygen species can inhibit ATP synthase and adenine nucle-
otide translocase. They can also cause peroxidation of unsaturated fatty acids in

O linked

acetylation, β

17 Protein kinase-C can complex with voltage-dependent anion channel (porin), adenine
nucleotide transporter, and hexokinase-2 as well as another with mitogen-activated protein kinase.
It phosphorylates mitochondrial aldehyde dehydrogenase-2 and α -ketoglutarate dehydrogenase
to reduce generation of reactive oxygen species. It also phosphorylates cytochrome-C oxidase
subunit-4, activates mitochondrial K AT P channel, and inhibits the mitochondrial permeability
transition pore. Protein kinase-B phosphorylates glycogen synthase kinase GSK3. Unphospho-
rylated (active) GSK3 phosphorylate cyclophilin-D to promote activation of the mitochondrial
permeability transition pore. Inhibition of GSK3 also reduces ATP entry into the mitochondria via
voltage-dependent anion channel, thereby reducing consumption of glycolytically generated ATP.
18 Connexin-43 translocates to mitochondria owing to heat shock protein HSP90 and translocase of
the mitochondrial outer membrane complex (TOM) to stimulate the mitochondrial K AT P channel.
Signal transducer and activator of transduction STAT3 can also enter mitochondria to regulate the
activity of the electron transport chain.
19 S-nitrosylation corresponds to addition of an nitric oxide group to protein thiols. S Nitrosothiols
derive from several mitochondrial proteins, such as complex-I, α subunit of the F 1 F 0 AT P a s e ,
α -ketoglutarate dehydrogenase, aconitase, creatine kinase, malate dehydrogenase, heat shock pro-
teins HSP60 and HSP70, electron transfer flavoprotein- α and - β , electron-transferring flavoprotein
dehydrogenase, subunit-5A of cytochrome-C oxidase, aldehyde dehydrogenase-2, succinate dehy-
drogenase subunit-A flavoprotein, very-long- and short-chain acylCoA dehydrogenase, carnitine
palmitoyltransferase-2, enoylCoA hydratase, and isocitrate dehydrogenase. Nitric oxide targets
complex-I, thereby reducing ROS generation. S Nitrosothiols inhibit complex-V, thus causing ATP
degradation by reverse mode of the ATPase. They also block irreversible oxidation of proteins.