ABSTRACT Differentiation from neural progenitor to mature neuron requires a metabolic switch, whereby mature neurons become almost entirely dependent upon oxidative phosphorylation (OXPHOS) for ATP production. Although more efficient with respect to ATP production, OXPHOS produces additional reactive oxygen species, as compared to glycolysis; thus, endogenous mechanisms to quench free radicals are essential for the maintenance of neuronal health. Melatonin is synthesized in neuronal mitochondria and has a dual role as a free radical scavenger and as an inhibitor of mitochondrial‐triggered cell death and proinflammatory pathways. Previously, we showed that loss of endogenous melatonin induced mitochondrial DNA (mtDNA) and cytochrome c (CytC) release triggering pathological inflammation and cell death pathways, respectively. Here we find that in mature neurons, but not undifferentiated neuronal cells, melatonin deficiency altered metabolic reprogramming in aralkylamine N ‐acetyltransferase knockout (AANAT‐KO) neurons as compared with neurons expressing AANAT. Interestingly, there are no differences in neural progenitors regardless of AANAT status. In addition, AANAT‐KO deficiency elevated BAK and BAX levels in AANAT‐KO neurons. Further, we found that exogenous melatonin treatment of AANAT‐KO cells during differentiation into mature neurons rescued metabolic reprogramming defects and restored normal BAK/BAX levels. Thus, we demonstrated that the metabolic reprogramming and subsequent consequences of the switch to OXPHOS that normally occurs during neuronal maturation are compromised by melatonin deficiency and rescued by melatonin supplementation.
Cypermethrin, a pyrethroid pesticide, has been shown to induce neurotoxicity in adult mammals. However, studies are also needed to explore its toxicity in developing brains and understand its mechanism of action in neurons.
In healthy neurons, a mitochondrial membrane potential gradient exists whereby membrane potential is highest in the soma and decreases with distance from the nucleus. Correspondingly, distal mitochondria have more oxidative damage and slower protein import than somal mitochondria. Due to these differences, distal mitochondria have an intrinsic first stressor that somal mitochondria do not have, resulting in synaptic mitochondrial vulnerability. A second stressor may result from mutant protein expression, situational stress, or aging, exacerbating vulnerable mitochondria activating stress responses. Under these conditions, distal mitochondria release cytochrome c and mitochondrial DNA, leading to compartmentalized sub-lethal caspase-3 activation and cytokine production. In this two-hit mitochondrial-driven synaptic loss model, synapse vulnerability during neurodegeneration is explained as a superposition of pre-existing lower synaptic mitochondrial membrane potential (hit one) with additional mitochondrial stress (hit two). This two-hit mechanism occurs in synaptic mitochondria, activating signaling pathways leading to synaptic degeneration, as a potential preamble to neuronal death.
Microglial activation is readily detected following cerebral ischemia/reperfusion-induced injury. Activated microglia polarize into either classic pro-inflammatory M1 or protective M2 microglia following ischemia/reperfusion-induced injury. Melatonin is protective immediately after ischemia/reperfusion-induced brain injury. However, the ability of melatonin to affect longer-term recovery from ischemic/reperfusion-induced injury as well as its ability to modulate microglia/macrophage polarization are unknown. The goal of this study is to understand the impact of melatonin on mice 14 days after injury, as well as to understand how melatonin affects microglial polarization of neuronal MT
Abstract Mitochondrial dysfunction is a common cause in pathophysiology of different neurodegenerative diseases. Elimination of dysfunctional and damaged mitochondria is a key requirement for maintaining homeostasis and bioenergetics of degenerating neurons. Using global microRNA (miRNA) profiling in a systemic rotenone model of Parkinson’s disease, we have identified miR-146a as upmost-regulated miRNA, which is known as inflammation regulatory miRNA. Here, we report the role of activated nuclear factor kappa beta (NF-kβ) in miR-146a-mediated downregulation of Parkin protein, which inhibits clearance of damaged mitochondria and induces neurodegeneration. Our studies have shown that 4-week rotenone exposure (2.5 mg/kg b.wt) induced oxidative imbalance-mediated NF-kβ activation in 1-year-old rat’s brain. Activated NF-kβ binds in promoter region of miR-146a gene and induces its transcription, which downregulates levels of Parkin protein. Decreased amount of Parkin protein results in accumulation of damaged and dysfunctional mitochondria, which further promotes the generation of reactive oxygen species in degenerating neurons. In conclusion, our studies have identified direct role of NF-kβ-mediated upregulation of miR-146a in regulating mitophagy through inhibition of the Parkin gene.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by extensive loss of neurons, and deposition of amyloid beta (Aβ) in the form of extracellular plaques. Aβ is considered to have critical role in synaptic loss and neuronal death underlying cognitive decline. Platelets contribute to 95% of circulating amyloid-precursor protein that releases Aβ into circulation. We have recently demonstrated that, Aβ active fragment containing amino acid sequence 25-35 (Aβ25-35) is highly thrombogenic in nature, and elicits strong aggregation of washed human platelets in RhoA-dependent manner. In the present study we evaluated the influence of fibrinogen on Aβ-induced platelet activation. Intriguingly, Aβ failed to induce aggregation of platelets suspended in plasma but not in buffer. Fibrinogen brought about dose-dependent decline in aggregatory response of washed human platelets elicited by Aβ25-35, which could be reversed by increasing doses of Aβ. Fibrinogen also attenuated Aβ-induced platelet responses like secretion, clot retraction, rise in cytosolic Ca+2 and reactive oxygen species (ROS). Fibrinogen prevented intracellular accumulation of full length amyloid beta peptide (Aβ42) in platelets as well as neuronal cells. We conclude that fibrinogen serves as a physiological check against the adverse effects of Aβ by preventing its interaction with cells.
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