Cordycepin Decreases Ischemia/Reperfusion Injury in Diabetic Hearts via Upregulating AMPK/Mfn2-dependent Mitochondrial Fusion

Abstract

Diabetes mellitus is considered to be a major risk factor for cardiovascular disease, the most common cause of death in diabetes. However, therapeutic strategies for myocardial protection in patients with diabetes are still limited. Cordycepin is a traditional Tibetan medicine with a long history of widespread use, and exerts a wide range of anti-tumor, anti-inflammatory, and anti-oxidative effects. In recent years, although the therapeutic potential of cordycepin has attracted the attention of researchers, it remains unknown whether cordycepin plays a protective role in myocardial ischemia/reperfusion (MI/R) injury in diabetic patients. Here, using a diabetic mouse model, we found that cordycepin protected diabetic hearts from MI/R injury by promoting mitochondrial fusion and Mfn2 expression. Our in vitro results showed that cordycepin enhanced Mfn2-medicated mitochondrial fusion, improved mitochondrial function, and reduced cardiomyocyte apoptosis in high-glucose/high-fat cultured simulated ischemia/reperfusion cardiomyocytes. Furthermore, we found that knockout of Mfn2 significantly blocked the cardioprotective effects of cordycepin in diabetic mice. Finally, an AMPK-dependent pathway was found to upregulate Mfn2 expression upon cordycepin treatment, indicating that cordycepin protected diabetic hearts via AMPK/Mfn2-dependent mitochondrial fusion. Collectively, our study firstly demonstrated that cordycepin could be a potential cardioprotective agent for MI/R injury, and we established a novel mechanism by which upregulated AMPK/Mfn2-dependent mitochondrial fusion contributes to the cardioprotective role of cordycepin.

BaoShenTongLuo formula protects against podocyte injury by regulating AMPK-mediated mitochondrial biogenesis in diabetic kidney disease

“…AMPK increases mitochondrial biogenesis by directly regulating PGC-1α expression, thus improving the OXPHOS capacity of tissues and cells [ 60 ]. Moreover, AMPK augments glucose metabolism, inhibits oxidative stress, and elevates MMP by regulating MFN2 to improve mitochondrial fusion and mitochondrial biogenesis function during mitochondrial energy crises [ 61 ]. Previous studies showed decreased p-AMPK levels in HG-treated podocytes [ 62 ].…”

Resveratrol Inhibits Zinc Deficiency-Induced Mitophagy and Exerts Cardioprotective Effects

“…Energy stress not only triggers mitochondrial ssion and autophagy, but also increases the number of MAMs., AMPK are transferred from the cytoplasm to mitochondria and MAMs, where AMPK directly interact with Mfn2 to regulate MAMs when mitochondrial ssion occurs [32]. Cordycepin reduces cardiac ischemia/reperfusion injury through upregulation of AMPK/Mfn2-dependent mitochondrial fusion [33].…”

Bioactive natural products in COVID-19 therapy

“…In terms of organ protection, cordycepin has unique advantages. For example, cordycepin plays a key role in long-term neuroprotection for traumatic brain injury (through inhibiting neutrophil infiltration and preserving neuroinflammation), (Wei et al, 2021) protecting diabetic hearts from ischemia/reperfusion injury (via up-regulating AMPK/Mfn2-dependent mitochondrial fusion and expression), (Yu et al, 2021) and ameliorating cerebral ischemic damage (via improving the memory ability, up-regulating the level of adenosine A1 receptors, and reducing dendritic morphology scathing). (Chen et al, 2021).…”