NR4A1 Aggravates Myocardial Ischaemia-Reperfusion Injury by Inhibiting OPA1-Mediated Mitochondrial Fusion

Mitochondrial fusion is an important process that protects the myocardium. However, mitochondrial fusion is often inhibited in myocardial ischaemia-reperfusion injury (IR). The upstream mechanism of this effect is unclear. Nuclear receptor subfamily 4 group A member 1 (NR4A1) can aggravate myocardial IR and increase the level of oxidative stress, thereby affecting mitochondrial function and morphology. Inhibiting NR4A1 can improve oxidative stress levels and mitochondrial function and morphology, thereby reducing IR. Downregulating NR4A1 increases the expression level of the mitochondrial fusion-related protein optic atrophy 1 (OPA1), which is associated with these benefits. Inhibiting OPA1 expression with MYLS22 abrogates the effects of NR4A1 downregulation on IR. Furthermore, NR4A1 disrupts mitochondrial dynamics and activates the STING and NF-κB pathways. Insufficient mitochondrial fusion and increased apoptosis and inflammatory reactions worsen irreversible damage to cardiomyocytes. In conclusion, NR4A1 can exacerbate IR by inhibiting OPA1, causing mitochondrial damage.

 

Comments:

Mitochondrial fusion plays a crucial role in maintaining the integrity and function of mitochondria, including those in the myocardium. In the context of myocardial ischemia-reperfusion injury (IR), however, mitochondrial fusion is often impaired, leading to detrimental effects on cardiac tissue. The precise upstream mechanisms contributing to this inhibition are not yet fully understood.

One potential factor involved in exacerbating myocardial IR is the nuclear receptor subfamily 4 group A member 1 (NR4A1). Increased NR4A1 activity has been associated with worsened myocardial IR and elevated levels of oxidative stress, which, in turn, negatively impact mitochondrial function and morphology. Inhibiting NR4A1 has been shown to improve oxidative stress levels, enhance mitochondrial function and morphology, and consequently reduce the severity of IR.

When NR4A1 is downregulated, the expression level of a mitochondrial fusion-related protein called optic atrophy 1 (OPA1) is increased. OPA1 is associated with the beneficial effects observed upon NR4A1 downregulation. However, it is important to note that inhibiting OPA1 expression with MYLS22 can reverse the effects of NR4A1 downregulation on IR, suggesting that OPA1 is a critical mediator of the protective effects conferred by reducing NR4A1 activity.

Moreover, NR4A1 has been found to disrupt mitochondrial dynamics and activate the STING (stimulator of interferon genes) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways. These alterations lead to insufficient mitochondrial fusion, increased apoptosis (programmed cell death), and inflammatory reactions, all of which contribute to the worsening of irreversible damage to cardiomyocytes during IR.

In summary, NR4A1 exacerbates myocardial IR by inhibiting OPA1 expression, resulting in mitochondrial damage. The disruption of mitochondrial dynamics, along with the activation of the STING and NF-κB pathways, leads to reduced mitochondrial fusion, increased apoptosis, and inflammation, ultimately exacerbating the injury to cardiomyocytes. Understanding these mechanisms may pave the way for the development of therapeutic strategies aimed at mitigating myocardial IR and protecting cardiac tissue.