Kv3.4 is modulated by HIF-1α to protect SH-SY5Y cells against oxidative stress-induced neural cell death

Abstract

The Kv3.4 channel is characterized by fast inactivation and sensitivity to oxidation. However, the physiological role of Kv3.4 as an oxidation-sensitive channel has yet to be investigated. Here, we demonstrate that Kv3.4 plays a pivotal role in oxidative stress-related neural cell damage as an oxidation-sensitive channel and that HIF-1α down-regulates Kv3.4 function, providing neuroprotection. MPP+ and CoCl2 are reactive oxygen species (ROS)-generating reagents that induce oxidative stress. However, only CoCl2 decreases the expression and function of Kv3.4. HIF-1α, which accumulates in response to CoCl2 treatment, is a key factor in Kv3.4 regulation. In particular, mitochondrial Kv3.4 was more sensitive to CoCl2. Blocking Kv3.4 function using BDS-II, a Kv3.4-specific inhibitor, protected SH-SY5Y cells against MPP+-induced neural cell death. Kv3.4 inhibition blocked MPP+-induced cytochrome c release from the mitochondrial intermembrane space to the cytosol and mitochondrial membrane potential depolarization, which are characteristic features of apoptosis. Our results highlight Kv3.4 as a possible new therapeutic paradigm for oxidative stress-related diseases, including Parkinson’s disease.

Qiliqiangxin attenuates hypoxia‐induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF‐1α‐dependent glycolysis

“…While QL intervention significantly elevated the ratio of aggregates/monomers compared with hypoxia group, such elevation was suppressed by HIF‐1α siRNA. Our results are in line with previous findings on the relationship between HIF‐1α and mitochondrial dysfunction 40, 41. It is known that ROS are mainly generated from complex III of the electron transport chain in the mitochondria, which are increased under hypoxic conditions 42.…”

“…Firstly, most glycolytic key enzymes are located in the cytosol, which favours immediate ATP supplies for actin rearrangement to facilitate angiogenesis and vesicular secretion and generates required intermediates necessary for cell growth and migration. 36,37 In the present study, we confirmed that down-regulated HIF-1a and 40,41 It is known that ROS are mainly generated from complex III of the electron transport chain in the mitochondria, which are increased under hypoxic conditions. 42 Activated HIF-1a expression could prevent cancer cells from ROS-induced apoptosis, 43 while knockdown of HIF-1a could induce cell apoptosis.…”

Hyperthermia Increases Neurotoxicity Associated with Novel Methcathinones

“…Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP, 100 µM) was used as a positive control. FCCP is an uncoupler of mitochondrial oxidative phosphorylation and therefore decreases ∆ψm [20]. SH-SY5 cells were exposed to FCCP for 4 h.…”

Therapeutic Effect of Mongolian Medicine RuXian‐I on Hyperplasia of Mammary Gland Induced by Estrogen/Progesterone through CRYAB‐Promoted Apoptosis

“…Recently, CRYAB has been found to exert multiple functions. In which, one of the most important function processes is the resistance to apoptosis induced by various stress factors, including oxidative stress [11] and endoplasmic reticulum stress [12]. When CRYAB is resistant to apoptosis in the selection of cells, HMG forms and, when it promotes oncogenic transformation, even leads to the onset of mammary tumors [13].…”