Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 198

Tabl e 5. 3. Prosurvival signaling pathways triggered by G-protein-coupled, protein Tyr kinase,
and cytokine receptors that target mitochondria (Source: [ 347 ]; GSK: glycogen synthase kinase;
HK: hexokinase; JaK: Janus kinase; mK AT P : mitochondrial ATP-sensitive K + channel; PKC:
protein kinase C; ROS: reactive oxygen species; STAT: signal transducer and activator of tran-
scription; : inhibition). Certain mitochondrial protein kinases in cardiomyocyte ensure protection

against ischemia-reperfusion damage. On the other hand, GSK3 phosphorylates porin, thereby

releasing HK2 from mitochondria and provoking an oxidative stress, in addition to activation of
mitochondrial permeability transition pore. On the other hand, PKC

β

phosphorylates porin, but
HK2 remains attached to porin. Kinase PKA phosphorylates also porin, thereby supressing its
opening.

Cytosol Mitochondrion

JaK-STAT3 STAT3 (mPTP )

MAP2K1/2-ERK1/2-NOS3-PKG PKC -PKB-HK2 (mPTP )

PI3K-PKB-ERK1/2-NOS3-PKG PKC -PKB-GSK3 β (GSK3 β )

PKC -PKB-ERK1/2-NOS3-PKG PKC -mK AT P -ROS-

-ROS-ERK1/2-GSK3

β (GSK3 β )

-ROS-PKC -GSK3 β (GSK3 β )

-ROS-PKC -AldH2

hexokinase-2, 11 The mPTP regulation depends on glycogen synthase

, 12 signal transducer and activator of transcription STAT3, 13 and sirtuin-3

kinase-3 β

[ 347 ]. 14
Brief periods of ischemia and reperfusion, the so-called ischemic preconditioning,
protect the myocardium against injury by a subsequent sustained ischemia. Binding
of HK2 to mitochondria rises after ischemic preconditioning and insulin stimulation
that activate PI3K-PKB axis. Deacetylation of cyclophilin-D (Lys166) by sirtuin-
3 reduces its PPIase activity [ 347 ]. Cardioprotection is also ensured by STAT3
phosphorylation (Tyr705) [ 347 ]. Factor STAT3 can attenuate ischemia-induced
ROS production in cardiomyocytes.

11 Four hexokinase isoforms exist (HK1-HK4). Subtypes HK1 and HK2 reside in both the cytosol
and mitochondria of cardiomocytes. They have different affinities for ATP and glucose.
12 Kinase GSK3

β

is constitutively active. its activity rises by phosphorylation (Tyr216). On the
other hand, phosphorylation at Ser9 by PKA, PKC, and ERK inactivates GSK3

β

. Phosphorylation
of Thr43 and Ser389 and Thr390 by ERK and P38MAPK, respectively, facilitate Ser9 phosphor-
ylation by other kinases. Cardioprotection by activated erythropoietin receptor or mitochondrial
ATP-sensitive K + channel before ischemia is associated with mitochondrial GSK3 β phosphoryla-

tion (Ser9; inactivation) [ 347 ].
13 Once it is phosphorylated, STAT3 binds to promoters of target genes. It localizes to the
mitochondrial matrix.
14 Sirtuins couple lysine deacetylation to NAD + hydrolysis. Three subtypes (SIRT3-SIRT5) lodge
in mitochondria. Once it is imported into mitochondria, the full-length sirtuin-3 is cleaved to
generate an active short form. It activates acetylCoA synthetase-2 (Lys642), long-chain acylCoA
dehydrogenase (LCAD; Lys42), and NDUF9 subunit of complex-I of mitochondrial electron
transport chain [ 347 ].