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Mitophagy alleviates ischemia/reperfusion-induced microvascular damage through improving mitochondrial quality

Dan Wu¹, Haizhe Ji², Wenjuan Du³

¹Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, China.

|February 3, 2022

Abstract:

The coronary arteries mainly function to perfuse the myocardium. When coronary artery resistance increases, myocardial perfusion decreases and myocardial remodeling occurs. Mitochondrial damage has been regarded as the primary cause of microvascular dysfunction. In the present study, we explored the effects of mitophagy activation on microvascular damage. Hypoxia/reoxygenation injury induced mitochondrial oxidative stress, thereby promoting mitochondrial dysfunction in endothelial cells. Mitochondrial impairment induced apoptosis, reducing the viability and proliferation of endothelial cells. However, supplementation with the mitophagy inducer urolithin A (UA) preserved mitochondrial function by reducing mitochondrial oxidative stress and stabilizing the mitochondrial membrane potential in endothelial cells. UA also sustained the viability and improved the proliferative capacity of endothelial cells by suppressing apoptotic factors and upregulating cyclins D and E. In addition, UA inhibited mitochondrial fission and restored mitochondrial fusion, which reduced the proportion of fragmented mitochondria within endothelial cells. UA enhanced mitochondrial biogenesis in endothelial cells by upregulating sirtuin 3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These results suggested that activation of mitophagy may reduce hypoxia/reoxygenation-induced cardiac microvascular damage by improving mitochondrial quality control and increasing cell viability and proliferation.

Insights

Activating mitophagy with urolithin A (UA) protects heart microvascular cells from hypoxia/reoxygenation injury. UA improves mitochondrial function and cell viability, reducing cardiac microvascular damage.

Area of Science:

Cardiovascular Biology
Mitochondrial Medicine
Cellular Physiology

Background:

Coronary artery resistance impacts myocardial perfusion and can lead to cardiac remodeling.
Mitochondrial damage is a key factor in microvascular dysfunction.
Hypoxia/reoxygenation injury impairs endothelial cell mitochondrial function, leading to apoptosis and reduced viability.

Purpose of the Study:

To investigate the protective effects of mitophagy activation on cardiac microvascular endothelial cells.
To determine if urolithin A (UA), a mitophagy inducer, can mitigate hypoxia/reoxygenation-induced damage.
To elucidate the mechanisms by which UA preserves mitochondrial quality and cell function.

Main Methods:

Induction of hypoxia/reoxygenation injury in endothelial cells.
Treatment with urolithin A (UA).
Assessment of mitochondrial function (oxidative stress, membrane potential, fission/fusion dynamics).
Evaluation of cell viability, proliferation, and apoptosis.
Analysis of mitochondrial biogenesis markers (SIRT3, PGC-1α).

Main Results:

Hypoxia/reoxygenation induced mitochondrial oxidative stress, dysfunction, and apoptosis in endothelial cells.
UA treatment preserved mitochondrial function by reducing oxidative stress and stabilizing membrane potential.
UA enhanced endothelial cell viability and proliferation by suppressing apoptosis and upregulating cyclins D and E.
UA modulated mitochondrial dynamics, inhibiting fission and promoting fusion.
UA boosted mitochondrial biogenesis via upregulation of sirtuin 3 and PGC-1α.

Conclusions:

Mitophagy activation, exemplified by UA treatment, offers a promising strategy to counteract hypoxia/reoxygenation-induced cardiac microvascular damage.
UA improves mitochondrial quality control, enhances endothelial cell survival, and promotes proliferation.
Targeting mitophagy may represent a novel therapeutic approach for conditions involving cardiac microvascular dysfunction.

Read full analysis

Keywords:

UA cardiac microvascular injury endothelial cells hypoxia/reoxygenation mitophagy

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