DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways

Abstract

Mitochondrial fission and selective mitochondrial autophagy (mitophagy) form an essential axis of mitochondrial quality control that plays a critical role in the development of cardiac ischemia-reperfusion (IR) injury. However, the precise upstream molecular mechanism of fission/mitophagy remains unclear. Dual-specificity protein phosphatase1 (DUSP1) regulates cardiac metabolism, but its physiological contribution in the reperfused heart, particularly its influence on mitochondrial homeostasis, is unknown. Here, we demonstrated that cardiac DUSP1 was downregulated following acute cardiac IR injury. In vivo, compared to wild-type mice, DUSP1 transgenic mice (DUSP1TG mice) demonstrated a smaller infarcted area and the improved myocardial function. In vitro, the IR-induced DUSP1 deficiency promoted the activation of JNK which upregulated the expression of the mitochondrial fission factor (Mff). A higher expression level of Mff was associated with elevated mitochondrial fission and mitochondrial apoptosis. Additionally, the loss of DUSP1 also amplified the Bnip3 phosphorylated activation via JNK, leading to the activation of mitophagy. Increased mitophagy overtly consumed mitochondrial mass resulting into the mitochondrial metabolism disorder. However, the reintroduction of DUSP1 blunted Mff/Bnip3 activation and therefore alleviated the fatal mitochondrial fission/mitophagy by inactivating the JNK pathway, providing a survival advantage to myocardial tissue following IR stress. The results of our study suggest that DUSP1 and its downstream JNK pathway are therapeutic targets for conferring protection against IR injury by repressing Mff-mediated mitochondrial fission and Bnip3-required mitophagy.

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

“…MKP1 is a threonine-tyrosine dualspecificity phosphatase that dephosphorylates and inactivates the MAPK-JNK pathway in kidney. Interestingly, the JNK pathway has been confirmed to be the upstream signal for mitochondrial fragmentation [18]. Other studies also suggest that CaMKII phosphorylation and Fis1 upregulation also participate into the regulation of mitochondrial fragmentation [44,45].…”

“…To acquire adenovirus-MKP1 (Ad-MKP1), the adenovirus plasmid was purchased from Vigene Bioscience (Rockville, MD, USA) [18]. Subsequently, 293T cells (purchased from ATCC) were used to generate the Ad-MKP1 using Lipofectamine 2000 (Thermo Fisher Scientific, Inc.).…”

“…In contrast, inhibition of JNK phosphorylation improves renal function in diabetic rats [17]. Notably, a subgroup of enzymes within the PTP superfamily, termed dual specificity phosphatases, are recently identified as upstream inhibitors of the MAPK pathway, which are now named the MAPK Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry phosphatases (MKPs) [18]. To date, 10 typical MKPs have been characterized, and MKP1 has been documented to have the ability to promote JNK inactivation.…”

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

“…The concept that fission or mitophagy modulates cell apoptosis is supported by a plethora of studies [8,51,52]. With respect to cell migration, several researchers reasoned that fission requires F-actin to form the potential contraction point at the surface of the mitochondria, which extensively consumes F-actin stress fibers, a necessary element for cell migration [53]. Moreover, oxidative stress and energy deletion, as a result of bad-structured mitophagy or fission, have the ability to induce the F-actin degradation via the regulation of cofilin, a depolymerization agent of F-actin [52].…”

SIRT3 Facilitates Amniotic Fluid Stem Cells to Repair Diabetic Nephropathy Through Protecting Mitochondrial Homeostasis by Modulation of Mitophagy

“…In oxidative stress-mediated cellular apoptosis, mitochondria have been documented to transmit apoptotic signals through the release of cytochrome c (cyt-c) into cytoplasm [18, 19]. Recently, several researchers have demonstrated that mitochondria use mitophagy, a mitochondrial autophagy system [20], to remove damaged mitochondria and inhibit mitochondrial apoptosis [21, 22]. However, whether mitophagy contributes to stem cell survival is unclear.…”