Deficiency of ROS‐Activated TRPM2 Channel Protects Neurons from Cerebral Ischemia‐Reperfusion Injury through Upregulating Autophagy

Abstract

Cerebral ischemia-reperfusion (I-R) transiently increased autophagy by producing excessively reactive oxygen species (ROS); on the other hand, activated autophagy would remove ROS-damaged mitochondria and proteins, which led to cell survival. However, the regulation mechanism of autophagy activity during cerebral I-R is still unclear. In this study, we found that deficiency of the TRPM2 channel which is a ROS sensor significantly decreased I-R-induced neuronal damage. I-R transiently increased autophagy activity both in vitro and in vivo. More importantly, TRPM2 deficiency decreased I-R-induced neurological deficit score and infarct volume. Interestingly, our results indicated that TRPM2 deficiency could further activate AMPK rather than Beclin1 activity, suggesting that TRPM2 inhibits autophagy by regulating the AMPK/mTOR pathway in I-R. In conclusion, our study reveals that ROS-activated TRPM2 inhibits autophagy by downregulating the AMPK/mTOR pathway, which results in neuronal death induced by cerebral I-R, further supporting that TRPM2 might be a potential drug target for cerebral ischemic injury therapy.

TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca 2+ -Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression

“…Accumulating evidence showed that TRPM2 is essentially involved in IR injury in many different types of tissues, such as the brain, heart, and kidneys [ 7 ]. For example, TRPM2 mediates brain IR injury by regulating autophagy [ 13 ] and zinc accumulation [ 15 ]. Moreover, TRPM2 mediates acute kidney injury via a mechanism that involves the activation of Rac Family Small GTPase 1 (RAC1), oxidative stress, and mitochondrial apoptotic pathways [ 12 ].…”

“…TRPM2 has been reported to be involved in many pathological processes, such as neurodegenerative [ 5 , 6 ] and vascular diseases [ 7 ] as well as tissue injury [ 8 – 10 ], by increasing intracellular Ca 2+ , triggering ROS production, and inducing inflammation. It is also known to play a detrimental role in ischemia–reperfusion (IR) injury in many types of tissues, such as the liver [ 11 ], kidney [ 12 ], and brain [ 13 – 15 ]. However, the role of TRPM2 in myocardial IR injury remains controversial.…”

TRPM2 protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction via modulating autophagy

“…Our recent work 63 shows that TRPM2 deficiency attenuates cerebral ischemia-reperfusion injury through enhancing autophagy via promoting the activity of AMPK, an upstream suppressor of mTOR. Here, we observed a marked increase in the phosphorylation level of AMPK after treatment with cisplatin, which however remained similar between Trpm2 -/- and WT MEFs Figure S5 C), implying that AMPK was not involved in the inhibition of cisplatin-induced autophagy due to TRPM2 deficiency.…”

Roles of TRPM channels in glioma

“… 87 Finally, other external activators include ROS, tumor necrosis factor-α (TNFα), reactive nitrogen (RNS), Zn2+, Falcon A, amyloid beta peptide, and H2O2. 88 …”