Drp1 regulates mitochondrial dysfunction and dysregulated metabolism in ischemic injury via Clec16a-, BAX-, and GSH- pathways

Abstract

The adaptation of mitochondrial homeostasis to ischemic injury is not fully understood. Here, we studied the role of dynamin-related protein 1 (Drp1) in this process. We found that mitochondrial morphology was altered in the early stage of ischemic injury while mitochondrial dysfunction occurred in the late stage of ischemia. Drp1 appeared to inhibit mitophagy by upregulating mito-Clec16a, which suppressed mito-Parkin recruitment and subsequently impaired the formation of autophagosomes in vascular tissues after ischemic injury. Moreover, ischemia-induced Drp1 activation enhanced apoptosis through inducing mitochondrial translocation of BAX and thereby increasing release of Cytochrome C to activate caspase-3/-9 signalling. Furthermore, Drp1 mediated metabolic disorders and inhibited the levels of mitochondrial glutathione to impair free radical scavenging, leading to further increases in ROS and the exacerbation of mitochondrial dysfunction after ischemic injury. Together, our data suggest a critical role for Drp1 in ischemic injury.

Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity

“…GFP-tagged Adenoviral vectors for Drp1 deletion (GTP-Ad-shDrp1) and Ad-shDrp1 were generated by Obio Technology (Shanghai, CHINA). Its interference effects on Drp1 has been reported in our previous study [ 6 ]. The Drp1 S616A mutation plasmid (S616A) and its blank control (Vector) was constructed by Genechem Biotechnology (Shanghai, CHINA).…”

“…Fifty specific-pathogen-free C57BL/6 male mice (~8 weeks old, 18–25 g) and Fifty Drp1 knockdown (Drp1 +/−) male mice (~8 weeks old, 20–23 g) were purchased from Shanghai Model Organisms Center, Inc (Shanghai, CHINA), and housed in the animal facility of Army Medical University (Chongqing, CHINA) for a week prior to the start of the experiments. The knockdown effects were proven in our previous studies [ 6 , 7 ]. The model preparation and treatment procedures in mice were the same as in rats.…”

“…We previously demonstrated that systemic treatments aimed at the control of mitochondrial homeostasis, including mitochondrial quantity and mitochondrial functions, may promote cell survival and functional recovery in ischemic/hypoxic injury [ [5] , [6] , [7] ]. As one of the early damaged organelles in ischemic/hypoxic injury, the mitochondrion plays a central role in cell material and energy metabolism.…”

“…Dynamin-related protein 1 (Drp1) is an important regulator of mitochondrial fission and affects the quantity of mitochondria. We have recently found that Drp1 plays an important role in the regulation of mitochondrial homeostasis after ischemia or hypoxia in various tissues [ [5] , [6] , [7] ]. Since ischemic/hypoxic injury causes aberrant mitochondrial fission and/or disrupted membrane integrity, Drp1 is a candidate drug target for the treatment of this condition.…”

Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1–Drp1 pathway

“…In neurons, the CB1 receptor is expressed in the plasma membrane and mitochondria 17,18 . Dynamin-related protein 1 (Drp1) is a key protein that regulates mitochondrial fission after brain ischemia 19 . Many studies have shown that downregulating Drp1 can induce neuroprotection after stroke 20,21 .…”