Neuroprotective effects of melatonin‐mediated mitophagy through nucleotide‐binding oligomerization domain and leucine‐rich repeat‐containing protein X1 in neonatal hypoxic–ischemic brain damage

Abstract

Hypoxia–ischemia (HI) is a major cause of brain damage in neonates. Mitochondrial dysfunction acts as a hub for a broad spectrum of signaling events, culminating in cell death triggered by HI. A neuroprotective role of melatonin (MT) has been proposed, and mitophagy regulation seems to be important for cell survival. However, the molecular mechanisms underlying MT‐mediated mitophagy during HI treatment are poorly defined. Nucleotide‐binding oligomerization domain and leucine‐rich repeat‐containing protein X1 (NLRX1) has emerged as a critical regulator of mitochondrial dynamics and neuronal death that participates in the pathology of diverse diseases. This study aimed to clarify whether NLRX1 participates in the regulation of mitophagy during MT treatment for hypoxic–ischemic brain damage (HIBD). We demonstrated that MT protected neonates from HIBD through NLRX1‐mediated mitophagy in vitro and in vivo. Meanwhile, MT upregulated the expression of NLRX1, Beclin‐1, and autophagy‐related 7 (ATG7) but decreased the expression of the mammalian target of rapamycin (mTOR) and translocase of the inner membrane of mitochondrion 23 (TIM23). Moreover, the neuroprotective effects of MT were abolished by silencing NLRX1 after oxygen–glucose deprivation (OGD). In addition, the downregulation of mTOR and upregulation of Beclin‐1 and ATG7 by MT were inhibited after silencing NLRX1 under OGD. In summary, MT modulates mitophagy induction through NLRX1 and plays a protective role in HIBD, providing insight into potential therapeutic targets for MT to exert neuroprotection.

Synthesis, DFT Study, and In Vitro Evaluation of Antioxidant Properties and Cytotoxic and Cytoprotective Effects of New Hydrazones on SH-SY5Y Neuroblastoma Cell Lines

“…The cells were pre-incubated with the tested compounds at concentrations 1, 10, and 20 µM for 90 min. Melatonin was used as a reference compound because of its well-established neuroprotective effects in various in vitro and in vivo models [ 17 ]. After 90 min pre-incubation with the test substances, SH-SY5Y cells were exposed to H 2 O 2 (1 mM, 15 min), as described in the Materials and Methods section.…”

Melatonin Ameliorates Post-Stroke Cognitive Impairment in Mice by Inhibiting Excessive Mitophagy

“…Studies have confirmed that MT exerts its protective effects on the nervous system by inducing mitophagy. In a neonatal hypoxic-ischemic encephalopathy model, intraperitoneal injection of MT (15 mg/kg) into pups 1 h before hypoxia induction upregulated the expression of NLRX1, which downregulated mTOR expression and promoted ATG7 and Beclin-1 expression to promote mitophagy and inhibit apoptosis [46]. In a model of glutamate-induced cytotoxicity in mouse hippocampal neurons, pretreatment with 10 −7 mol/L MT for 2 h mediated mitophagy via the Beclin-1/Bcl-2 pathway, thus exerting antioxidative stress and neuroprotective effects [47].…”

Possible correlated signaling pathways with chronic urate nephropathy: A review

“…Mitochondrial biosynthesis and mitochondrial autophagy flow after injury are the key links in the repair of renal tubular injury. NLRX1 is a member of the NLR family, which plays an important role in regulating immune response, promoting ROS production, mitochondrial damage, autophagy, [12] apoptosis [13] and so on. Because the N-terminal of NLRX1 contains a mitochondrial localization sequence, it becomes the first NLR located in mitochondria and plays an important role in mitochondrial directional transmission.…”