Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 197

(1) a dimer of voltage-dependent anion channels (VDAC), 7 or porins, in the
mitochondrial outer membrane (MOM); and (2) a dimer of adenine nucleotide
translocases (ANT) 8 linked to (3) mitochondrial inorganic phosphate (Pi) carrier
SLC25a3 9 in the mitochondrial inner membrane (MIM) [ 347 ]. Both VDAC and
ANT serve as regulators of the mPTP in cooperation with the matrix protein,
cyclophilin-D (CyPd). 10
Adenine nucleotide translocase interacts with cyclophilin-D and SLC25a3
carrier. Binding of cyclophilin-D to mPTP increases mPTP sensitivity to Ca 2 +
ion. Elevation of matrix Ca 2 + concentration triggers mPTP opening and cytosolic-
open ANT conformation, thereby favoring Ca 2 + sensitivity of the mitochondrial
permeability transition pore.
Opening of mitochondrial permeability transition pore causes mitochondrial
swelling, hence rupture of the mitochondrial outer membrane and release of
cytochrome-C into the cytosol, triggering apoptosome formation and myocyte
death. Multiple prosurvival signals prevents mPTP opening (Table 5.3 ). On the other
hand, mPTP remains closed during ischemia and opens shortly after reperfusion.
Moreover, ischemia-reperfusion events promote CyPd-PiC-ANT interaction in
cardiomyocytes.
7 Three VADC isoforms (VDAC1-VDAC3) are encoded by distinct genes. Subtype VDAC1
is the most abundant isoform in most cells. It interacts with multiple proteins involved in
energy production, formation of cytoskeletal networks, and apoptosis. In the mitochondrial outer
membrane, VDAC binds to hexokinase-2 that supports ADP transport into mitochondria and ADP
production from phosphorylation of glucose in a nearby location [ 347 ].
8 The ANT family comprises 4 isoforms encoded by different nuclear genes. Isoform ANT1 is
predominant in the heart and muscle [ 347 ]. Subtype ANT3 is produced at low levels whatever
the cell type. Both ANT2 and ANT4 are synthesized during cell proliferation and in the brain,
liver, and testis, respectively. Whereas ANT1 and ANT3 are antisurvival factors, ANT2 and ANT4
are prosurvival agents. Adenine nucleotide translocase exchanges ADP 3 − and ATP 4 − between the
mitochondrial matrix and intermembrane space. It is stimulated by ADP 3 − ,ATP 4 − , and BCL2.
9 Two SLC25a3 isoforms (SLC25a3a-SLC25a3b) are created by alternative splicing from the
SLC25A3 transcript. Isoform SLC25a3a is synthesized in cardiac and skeletal muscles; SLC25a3b
is ubiquitous. Carrier SLC25a3 acts as a Pi-H + symporter and/or Pi-OH − antiporter [ 347 ]. In
any case, it carries cytosolic inorganic phosphate to the mitochondrial matrix, where inorganic
phosphate is used for ATP synthesis.
10 Cyclophilin-D is a peptidyl prolyl cis-trans isomerase encoded by the PPIf gene. It is the single
isoform that lodges in the mitochondrial matrix. It precludes elevation of mitochondrial Ca 2 +
concentration. It interacts with SLC25a3 and ANT, thus modifying mPTP sensitivity to Ca 2 + and
inorganic phosphate [ 347 ]. It also links to mitochondrial ATPase and reduces its activity.