Dynamics of Mitochondrial Redox and Energy Networks: Insights from an Experimental–Computational Synergy - Systems Biology of Metabolic and Signaling Networks - page 128

Experiment Model

a c

24 150

8.0

ATPi IK ATP

ΔΨ m

120

7.8

18

90 7.6

12

60

7.4

6

30

7.2

0

0 7.0

120

130 140 150 160

b

660

60

30

30

0

0

-30

-30

APD 90 =43mS

APD 90 =170mS

-60

-60

-90

-90

124.0 124.1 124.2 124.3 138.0 138.1 138.2 138.3

Time (msec)

Fig. 5.10 Effects of mitochondrial oscillation on the electrical excitability of the cardiomyocyte
(a) Action potentials (AP, upper panel ) evoked by brief current injections were recorded in current
clamp mode during whole-cell patch clamp while simultaneously imaging ΔΨ

m with TMRE
( lower panel ). During a synchronized cell-wide depolarization-repolarization cycle, the AP
shortened in synchrony with fast mitochondrial depolarization, and the cell became unexcitable
in the fully depolarized state (remaining upward spikes are from the stimulus only). Recovery of
ΔΨ m coincided with restoration of AP. (b) Temporal correlation between the AP duration at 90 %

repolarization and m . The current-voltage relationship of the oscillatory membrane current fits

the profile of the sarcolemmal K ATP current (Aon et al. 2003 ). (c) Simulations of

ΔΨ

m , cytoplas-
mic ATP concentration ([ATP]i) and sarcolemmal K ATP current during oscillations triggered by
oxidative stress, and comparison of APs during polarized and depolarized states. Modified from
Aon, Cortassa, Marban, O'Rourke (2003) J Biol Chem 278, 44735-44, and Zhou, Cortassa, Wei,
Aon, Winslow, O'Rourke (2009) Biophys J 97, 1843-1852

ΔΨ

triggered by ROS was shown experimentally to be coupled to the opening of
sarcolemmal ATP-sensitive potassium (K ATP ) channels, contributing to electrical
dysfunction during ischemia-reperfusion. K ATP channels have a low open proba-
bility under physiological conditions, but are rapidly activated during ischemia or
metabolic inhibition (Lederer et al. 1989 ; Noma 1983 ).
Figure 5.10 shows that during the depolarized phase of the oscillation, the AP
interval shortens as a consequence of the activation of sarcolemmal K ATP currents
rendering the myocyte electrically inexcitable during the nadir of

ΔΨ m (Akar
et al. 2005 ; Aon et al. 2003 ). The fact that these effects were mediated by ΔΨ m

depolarization was indicated by inhibition of the IMAC-mediated mitochondrial
oscillations with 4 0 -chlorodiazepam (4 0 -Cl-DZP) an intervention that concomitantly
reestablished and stabilized the sarcolemmal AP.
Highly nonlinear interactions are involved in the mitochondrial oscillation-
driven inexcitability of the cardiac cell, including communication through transport