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Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review)

  • Authors:
    • Yan Wang
    • Baowei Feng
    • Yanting Wu
    • Zongle Sun
    • Hao Yuan
    • Wei Chen
    • Chang Zhao
    • Zhi Liu
  • View Affiliations / Copyright

    Affiliations: College of Integration of Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China, College of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China, Changchun Humanities and Sciences College, Changchun, Jilin 130118, P.R. China, College of the First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].
  • Article Number: 34
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    Published online on: December 2, 2025
       https://doi.org/10.3892/ijmm.2025.5705
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Abstract

Ischemic heart disease remains the leading cause of global disease burden among cardiovascular disorders. In addition to cardiomyocyte injury, ischemia-reperfusion (I/R)-induced microvascular damage plays a crucial role in determining tissue dysfunction and overall prognosis. Mitochondria-associated endoplasmic reticulum membranes (MAMs), specialized contact sites between the ER and mitochondria, are now recognized as key regulators of cardiovascular pathophysiology. The present review summarized current knowledge of the structure of MAMs and their effects on endothelial cells under hypoxia/reoxygenation conditions. Particular attention was given to their role in regulating mitochondrial quality control processes, including fission, fusion, oxidative stress, mitophagy and Ca2+ homeostasis, within the context of cardiac microvascular I/R injury. Targeting MAMs may represent a promising strategy for microvascular protection in ischemic heart disease.
View Figures

Figure 1

The pathological functions of
mitochondrial dynamics, mitochondrial oxidative stress, mitophagy
and calcium overload in cardiac microvascular I/R injury. I/R,
ischemia-reperfusion; MAM, mitochondria-associated endoplasmic
reticulum membrane; ROS, reactive oxygen species; mtDNA;
mitochondrial DNA; mROS, mitochondrial ROS.

Figure 2

MAMs mediate the regulation of
oxidative stress during the pathological process of cardiac
microvascular I/R injury. Following cardiac microvascular ischemia,
excessive Ca2+ transfer from the ER to the mitochondria
induces calcium overload, leading to elevated mROS production.
Excessive ROS stimulation further releases apoptosis-related
proteins into the cytoplasm and activates the apoptotic cascade.
During cardiac ischemia-reperfusion, necrotic cardiomyocytes
release ATP, which binds to P2X7 receptors on neighboring
non-ischemic cardiomyocytes. This interaction induces potassium ion
(K+) efflux, lowering cytoplasmic K+
concentration. The resulting hypokalemic state activates NEK7,
promoting inflammasome assembly and NLRP3 activation. Nox4 is
increased at the MAM during cellular stress, where it encourages
Akt-mediated phosphorylation of IP3R to prevent calcium
transfer and subsequent mPTP-dependent cell death. Furthermore,
MAMs are currently the only known assembly platform for the NLRP3
inflammasome and are important mediators of oxidative damage.
Structural proteins within MAMs, such as Ero1 and p66Shc, play a
direct role in redox crosstalk between the mitochondria and ER,
further exacerbating ROS generation. MAM, Mitochondria-associated
endoplasmic reticulum membrane; I/R, ischemia-reperfusion; ER mROS,
mitochondrial ROS; ROS, reactive oxygen species; NEK7, NIMA-related
kinase 7; mtDNA; mitochondrial DNA; IP3R,
1,4,5-trisphosphate receptors; NLRP3, pyrin domain-containing
receptor 3; mPTP, mitochondrial permeability transition pore; Ero1,
endoplasmic reticulum oxidoreductase 1; p66Shc, 66-kDa isoform of
the growth factor adaptor Shc.

Figure 3

During I/R injury, DUSP1 and NR4A1
play distinct roles in the activation of mitophagy: DUSP1 induces
mitophagy by promoting BNIP3 phosphorylation, whereas NR4A1
suppresses mitophagy through inhibition of FUNDC1 activity. These
alterations contribute to mitochondrial energy disorder, ultimately
leading to endothelial cell apoptosis and microvascular
dysfunction. I/R, ischemia-reperfusion; DUSP1, dual-specificity
phosphatase 1; NR4A1, nuclear receptor 4A1; FUNDC1, FUN14
domain-containing protein 1; BNIP3, BCL2/adenovirus E1B 19 kDa
interacting protein 3.

Figure 4

MAMs play a critical role in
regulating mitophagy during microvascular I/R injury. The mechanism
targets of autophagosome markers (ATG) 5/14 and mTOR2 are key
inducers of autophagy. For example, STX 17, located on the
autophagosome outer membrane can bind to ATG14 and transfer it to
MAM until autophagosome is complete. Under ischemic and hypoxic
conditions, PINK1 accumulates on the damaged OMM and recruits
Parkin from the cytosol, which then ubiquitinates OMM proteins such
as MFN2 and VDAC to promote mitophagy. As a mitochondrial membrane
protein, FUNDC1 interacts with LC3 during hypoxic stress to
facilitate mitochondrial mitophagy. It also recruits Drp1 to MAMs
and stimulates the elimination of defective mitochondria. In
addition, Beclin1, an upstream regulator of mitophagy, protects the
microvascular against I/R injury. MAM, mitochondria-associated
endoplasmic reticulum membrane; I/R, ischemia-reperfusion; STX 17,
syntaxin 17; ATG14, autophagy related 14; OMM, outer mitochondrial
membrane; MFN2, mitofusin-2; VDAC, voltage-dependent anion channel;
Drp1, dynamin-related protein 1

Figure 5

MAMs regulate calcium homeostasis
during microvascular I/R. During hypoxia/reoxygenation, an
increased interaction of the CYPD-VDAC1-GRP75-IP3R1
Ca2+ complex leads to mitochondrial Ca2+
overload and cardiomyocyte mortality. The activity of SERCA and
CRT, responsible for Ca2+ reuptake into the endoplasmic
reticulum and Ca2+ storage in the ER, is inhibited. The
complex of VAPB-PTPIP51-MCU mediates the transport of
Ca2+ from the endoplasmic reticulum to mitochondria.
GSK-3β can be recruited to the MAM, where it regulates
IP3R1-mediated calcium release. This regulation promotes
mitochondrial Ca2+ accumulation and induces the opening
of the mPTP. Sig-1R is a specific chaperone localized at MAMs and
is functionally associated with the IP3R-GRP75-VDAC-MCU
calcium signaling axis. Therapeutically, TMEM215 protects
endothelial cells by inhibiting BIK. Similarly, HINT2 protects
CMECs during ischemia by directly inhibiting the MCU complex,
reducing mitochondrial Ca2+ overload and preserving
cardiac function. MAM, mitochondria-associated endoplasmic
reticulum membrane; I/R, ischemia-reperfusion; CYPD, cyclophilin D;
VDAC1, voltage-dependent anion channel 1; GRP75, glucose-regulated
protein 75; IP3R, 1,4,5-trisphosphate receptors; SERCA,
sarco/endoplasmic reticulum Ca2+ ATPase; CRT,
calreticulin; ER, endoplasmic reticulum; VAPB, vesicle-associated
membrane protein-associated protein-B; PTPIP51, protein tyrosine
phosphatase-interacting protein-51; MCU, mitochondrial calcium
uniporter; GSK-3β, glycogen synthase kinase-3β; mPTP, mitochondrial
permeability transition pore; Sig-1R, σ-1 receptor; TMEM215,
transmembrane protein 215; BIK, Bcl-2-interacting killer; HINT2,
histidine triad nucleotide-binding protein 2; CMECs, cardiac
microvascular endothelial cells.

Figure 6

Mitochondrial dysfunction plays a
central role in the apoptosis of endothelial cells during cardiac
microvascular I/R injury. Specifically, ischemia/reperfusion
induces mitochondrial oxidative stress and structural remodeling in
microvascular endothelial cells, characterized by excessive
mitochondrial fission, impaired fusion and overproduction of mROS.
These alterations facilitate the opening of the mPTP and calcium
overload, leading to the release of Cyt-C, the activation of
caspase-9 and caspase-3 and ultimately, endothelial apoptosis and
microvascular damage. Furthermore, potential therapeutic
interventions, such as the Shuangshen Ningxin formula, melatonin,
empagliflozin, Shenlian extract and pinacidil have been shown to
mitigate mROS generation, stabilize mPTP function and restore
mitochondrial dynamics, thereby protecting endothelial cells and
alleviating cardiac microvascular I/R injury. I/R,
ischemia-reperfusion; m/mitoROS, mitochondrial reactive oxygen
species; mPTP, mitochondrial permeability transition pore; Cyt-C,
cytochrome c.

Figure 7

MAMs play a central role in
maintaining mitochondrial homeostasis during cardiac microvascular
I/R injury. MAMs function as structural and signaling hubs that
coordinate mitochondrial dynamics, oxidative stress, mitophagy and
Ca2+ homeostasis. Specifically, the Drp1 and MFN1/2-OPA1
complexes mediate mitochondrial fission and fusion. MFN1 and MFN2
are not only central to mitochondrial structure but are also
closely associated with angiogenic signaling pathways in vascular
endothelial cells. MAM-localized p66Shc and Ero1α contribute to
reactive oxygen species (ROS) generation and Ca2+
influx, activating NLRP3 inflammasome-mediated inflammatory
cascades. The IP3R-Grp75-VDAC1 complex regulates
Ca2+ transfer between the endoplasmic reticulum and
mitochondria, while Sig-1R and VAPB-PTPIP51 tethers stabilize
inter-organelle communication and prevent Ca2+ overload.
Additionally, MAMs serve as key platforms for PINK1/Parkin- and
LC3-dependent mitophagy, mediated through FUNDC1, NIX and BNIP3.
Dysregulation of these pathways leads to excessive ROS
accumulation, Ca2+ imbalance and mitochondrial
dysfunction, ultimately contributing to endothelial apoptosis and
impaired microvascular repair following cardiac
ischemia-reperfusion (I/R) injury. MAM, mitochondria-associated
endoplasmic reticulum membrane; I/R, ischemia-reperfusion; MFN1,
mitofusin-1; MFN2, mitofusin-2; OPA1, optic atrophy 1.
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Copy and paste a formatted citation
Spandidos Publications style
Wang Y, Feng B, Wu Y, Sun Z, Yuan H, Chen W, Zhao C and Liu Z: Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review). Int J Mol Med 57: 34, 2026.
APA
Wang, Y., Feng, B., Wu, Y., Sun, Z., Yuan, H., Chen, W. ... Liu, Z. (2026). Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review). International Journal of Molecular Medicine, 57, 34. https://doi.org/10.3892/ijmm.2025.5705
MLA
Wang, Y., Feng, B., Wu, Y., Sun, Z., Yuan, H., Chen, W., Zhao, C., Liu, Z."Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review)". International Journal of Molecular Medicine 57.2 (2026): 34.
Chicago
Wang, Y., Feng, B., Wu, Y., Sun, Z., Yuan, H., Chen, W., Zhao, C., Liu, Z."Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 34. https://doi.org/10.3892/ijmm.2025.5705
Copy and paste a formatted citation
x
Spandidos Publications style
Wang Y, Feng B, Wu Y, Sun Z, Yuan H, Chen W, Zhao C and Liu Z: Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review). Int J Mol Med 57: 34, 2026.
APA
Wang, Y., Feng, B., Wu, Y., Sun, Z., Yuan, H., Chen, W. ... Liu, Z. (2026). Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review). International Journal of Molecular Medicine, 57, 34. https://doi.org/10.3892/ijmm.2025.5705
MLA
Wang, Y., Feng, B., Wu, Y., Sun, Z., Yuan, H., Chen, W., Zhao, C., Liu, Z."Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review)". International Journal of Molecular Medicine 57.2 (2026): 34.
Chicago
Wang, Y., Feng, B., Wu, Y., Sun, Z., Yuan, H., Chen, W., Zhao, C., Liu, Z."Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 34. https://doi.org/10.3892/ijmm.2025.5705
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