Oxidative stress in the mitochondrial matrix underlies ischemia/reperfusion-induced mitochondrial instability

Soroosh Solhjoo*, Ting Liu, Agnieszka Sidor, Dong I. Lee, Brian O'Rourke, Charles Steenbergen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Ischemia and reperfusion affect multiple elements of cardiomyocyte electrophysiology, especially within the mitochondria. We previously showed that in cardiac monolayers, upon reperfusion after coverslip-induced ischemia, mitochondrial inner membrane potential (ΔΨ) unstably oscillates between polarized and depolarized states, and ΔΨ instability corresponds with arrhythmias. Here, through confocal microscopy of compartment-specific molecular probes, we investigate the mechanisms underlying the postischemic ΔΨ oscillations, focusing on the role of Ca2+ and oxidative stress. During reperfusion, transient ΔΨ depolarizations occurred concurrently with periods of increased mitochondrial oxidative stress (5.07 ± 1.71 oscillations/15 min, N = 100). Supplementing the antioxidant system with GSH monoethyl ester suppressed ΔΨ oscillations (1.84 ± 1.07 oscillations/15 min, N = 119, t test p = 0.027) with 37% of mitochondrial clusters showing no ΔΨ oscillations (versus 4% in control, odds ratio = 14.08, Fisher's exact test p < 0.001). We found that limiting the production of reactive oxygen species using cyanide inhibited postischemic ΔΨ oscillations (N = 15, t test p < 10−5). Furthermore, ΔΨ oscillations were not associated with any discernable pattern in cell-wide oxidative stress or with the changes in cytosolic or mitochondrial Ca2+. Sustained ΔΨ depolarization followed cytosolic and mitochondrial Ca2+ increase and was associated with increased cell-wide oxidative stress. Collectively, these findings suggest that transient bouts of increased mitochondrial oxidative stress underlie postischemic ΔΨ oscillations, regardless of Ca2+ dynamics.

Original languageEnglish
Article number102780
JournalJournal of Biological Chemistry
Volume299
Issue number1
DOIs
StatePublished - Jan 2023
Externally publishedYes

Keywords

  • GSH redox potential
  • calcium imaging
  • cardiac monolayers
  • coverslip-induced ischemia
  • inner membrane potential oscillations
  • neonatal rat ventricular myocytes
  • optical mapping
  • reactive oxygen species
  • reentry arrhythmias
  • reperfusion

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