Open Access
Open access
Wiley
Journal of the American Heart Association
,  volume 11 ,  issue 13

Inhibiting Succinate Release Worsens Cardiac Reperfusion Injury by Enhancing Mitochondrial Reactive Oxygen Species Generation

Publication type: Journal Article
Publication date: 2022-06-29
Wiley
scimago Q1
wos Q1
SJR: 2.189
CiteScore: 8.5
Impact factor: 5.3
ISSN: 20479980
Cardiology and Cardiovascular Medicine
Abstract
Background
The metabolite succinate accumulates during cardiac ischemia. Within 5 minutes of reperfusion, succinate returns to baseline levels via both its release from cells and oxidation by mitochondrial complex II. The latter drives reactive oxygen species (ROS) generation and subsequent opening of the mitochondrial permeability transition (PT) pore, leading to cell death. Targeting succinate dynamics (accumulation/oxidation/release) may be therapeutically beneficial in cardiac ischemia–reperfusion (IR) injury. It has been proposed that blocking MCT1 (monocarboxylate transporter 1) may be beneficial in IR injury, by preventing succinate release and subsequent engagement of downstream inflammatory signaling pathways. In contrast, herein we hypothesized that blocking MCT1 would retain succinate in cells, exacerbating ROS generation and IR injury.
Methods and Results
Using the mitochondrial ROS probe mitoSOX and a custom‐built murine heart perfusion rig built into a spectrofluorometer, we measured ROS generation in situ during the first moments of reperfusion. We found that acute MCT1 inhibition enhanced mitochondrial ROS generation at reperfusion and worsened IR injury (recovery of function and infarct size). Both of these effects were abrogated by tandem inhibition of mitochondrial complex II, suggesting that succinate retention worsens IR because it drives more mitochondrial ROS generation. Furthermore, using the PT pore inhibitor cyclosporin A, along with monitoring of PT pore opening via the mitochondrial membrane potential indicator tetramethylrhodamine ethyl ester, we herein provide evidence that ROS generation during early reperfusion is upstream of the PT pore, not downstream as proposed by others. In addition, pore opening was exacerbated by MCT1 inhibition.
Conclusions
Together, these findings highlight the importance of succinate dynamics and mitochondrial ROS generation as key determinants of PT pore opening and IR injury outcomes.
Found 
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Milliken A. S., Nadtochiy S. M., BROOKES P. A. Inhibiting Succinate Release Worsens Cardiac Reperfusion Injury by Enhancing Mitochondrial Reactive Oxygen Species Generation // Journal of the American Heart Association. 2022. Vol. 11. No. 13.
GOST all authors (up to 50) Copy
Milliken A. S., Nadtochiy S. M., BROOKES P. A. Inhibiting Succinate Release Worsens Cardiac Reperfusion Injury by Enhancing Mitochondrial Reactive Oxygen Species Generation // Journal of the American Heart Association. 2022. Vol. 11. No. 13.
RIS |
Cite this
RIS Copy
TY - JOUR
DO - 10.1161/jaha.122.026135
UR - https://doi.org/10.1161/jaha.122.026135
TI - Inhibiting Succinate Release Worsens Cardiac Reperfusion Injury by Enhancing Mitochondrial Reactive Oxygen Species Generation
T2 - Journal of the American Heart Association
AU - Milliken, Alexander S.
AU - Nadtochiy, Sergiy M.
AU - BROOKES, PAUL A.
PY - 2022
DA - 2022/06/29
PB - Wiley
IS - 13
VL - 11
PMID - 35766275
SN - 2047-9980
ER -
BibTex
Cite this
BibTex (up to 50 authors) Copy
@article{2022_Milliken,
author = {Alexander S. Milliken and Sergiy M. Nadtochiy and PAUL A. BROOKES},
title = {Inhibiting Succinate Release Worsens Cardiac Reperfusion Injury by Enhancing Mitochondrial Reactive Oxygen Species Generation},
journal = {Journal of the American Heart Association},
year = {2022},
volume = {11},
publisher = {Wiley},
month = {jun},
url = {https://doi.org/10.1161/jaha.122.026135},
number = {13},
doi = {10.1161/jaha.122.026135}
}