Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury.

Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers chronic neurodegeneration persisting 17 months later, equivalent to many human decades. We show that increased mitochondrial fission after mouse TBI is related to increased brain levels of mitochondrial fission 1 protein (Fis1) and that brain Fis1 is also elevated in human TBI.

Neuroprotective signaling by hydrogen sulfide and its dysregulation in Alzheimer's disease.

The ancient messenger molecule hydrogen sulfide (HS) modulates myriad signaling cascades and has been conserved across evolutionary boundaries. Although traditionally known as an environmental toxin, HS is also synthesized endogenously to exert modulatory and homeostatic effects in a broad array of physiologic functions. Notably, HS levels are tightly physiologically regulated, as both its excess and paucity can be toxic.

Neuroprotective Roles of the Biliverdin Reductase-A/Bilirubin Axis in the Brain.

Biliverdin reductase-A (BVRA) is a multi-functional enzyme with a multitude of important roles in physiologic redox homeostasis. Classically, BVRA is well known for converting the heme metabolite biliverdin to bilirubin, which is a potent antioxidant in both the periphery and the brain. However, BVRA additionally participates in many neuroprotective signaling cascades in the brain that preserve cognition.

Hydrogen sulfide: Recent development of its dual donors and hybrid drugs.

Hydrogen sulfide (H S) is an important gaseous signalling molecule known to be critically involved in regulating cellular redox homeostasis. As the beneficial and therapeutic effects of H S in pathophysiology, such as in cardiovascular and neurodegenerative diseases, have emerged, so too has the drive for the development of H S-releasing compounds (aka donors) and their therapeutic applications. Most reported donor compounds singularly release H S through biocompatible triggers.

Inositol polyphosphate multikinase modulates redox signaling through nuclear factor erythroid 2-related factor 2 and glutathione metabolism.

Maintenance of redox balance plays central roles in a plethora of signaling processes. Although physiological levels of reactive oxygen and nitrogen species are crucial for functioning of certain signaling pathways, excessive production of free radicals and oxidants can damage cell components. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling cascade is the key pathway that mediates cellular response to oxidative stress.

Hypoxia sensing requires HS-dependent persulfidation of olfactory receptor 78.

Oxygen (O) sensing by the carotid body is critical for maintaining cardiorespiratory homeostasis during hypoxia. Hydrogen sulfide (HS) signaling is implicated in carotid body activation by low O. Here, we show that persulfidation of olfactory receptor 78 (Olfr78) by HS is an integral component of carotid body activation by hypoxia.

Hydrogen sulfide signalling in neurodegenerative diseases.

The gaseous neurotransmitter hydrogen sulfide (H S) exerts neuroprotective efficacy in the brain via post-translational modification of cysteine residues by sulfhydration, also known as persulfidation. This process is comparable in biological impact to phosphorylation and mediates a variety of signalling events. Unlike conventional neurotransmitters, H S cannot be stored in vesicles due to its gaseous nature.

Protective Roles of Hydrogen Sulfide in Alzheimer's Disease and Traumatic Brain Injury.

The gaseous signaling molecule hydrogen sulfide (HS) critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. HS has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions.

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury.

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood.

DUB'ling down uncovers an X-linked vulnerability in Alzheimer's disease.

Although women are at higher risk for Alzheimer's disease and other tauopathies, the underlying mechanisms are unclear. In this issue of Cell, Yan et al. show that aberrantly high activity of X-linked USP11 deubiquitinase in women impairs clearance of tau, the principal component of neurofibrillary tangles in Alzheimer's disease.

Mutant Huntingtin Derails Cysteine Metabolism in Huntington's Disease at Both Transcriptional and Post-Translational Levels.

Cysteine is a semi-essential amino acid that not only plays an essential role as a component of protein synthesis, but also in the generation of numerous sulfur-containing molecules such as the antioxidant glutathione and coenzyme A. We previously showed that the metabolism of cysteine is dysregulated in Huntington's disease (HD), a neurodegenerative disorder triggered by the expansion of polyglutamine repeats in the protein huntingtin. In this study, we showed that cysteine metabolism is compromised at multiple levels in HD, both transcriptional and post-translational.

Cystathionine γ-lyase exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation.

Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world's population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme cystathionine γ-lyase (CTH) is upregulated in humans and mice with H.

Cysteine metabolism and hydrogen sulfide signaling in Huntington's disease.

The semi-essential amino acid, cysteine, plays important roles in both essential cellular processes as well as in modulation of signaling cascades. Cysteine is obtained both from the diet as well as generated endogenously via the transsulfuration pathway. Cysteine is further utilized in protein synthesis and biosynthesis of various sulfur containing molecules.

Ergothioneine: A Stress Vitamin with Antiaging, Vascular, and Neuroprotective Roles?

Ergothioneine (ET) is an unusual sulfur-containing amino acid derived from histidine, acquired predominantly from food. Its depletion is associated with deleterious consequences in response to stress stimuli in cell culture models, prompting us to classify it as a vitamin in 2010, which was later supported by studies. ET is obtained from a variety of foods and is taken up by a selective transporter.

Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington's Disease.

Huntington's disease (HD) is caused by expansion of polyglutamine repeats in the protein huntingtin, which affects the corpus striatum of the brain. The polyglutamine repeats in mutant huntingtin cause its aggregation and elicit toxicity by affecting several cellular processes, which include dysregulated organellar stress responses. The Golgi apparatus not only plays key roles in the transport, processing, and targeting of proteins, but also functions as a sensor of stress, signaling through the Golgi stress response.

Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome.

Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called "long COVID-19," reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance.

Neuroprotective Roles of the Reverse Transsulfuration Pathway in Alzheimer's Disease.

The reverse transsulfuration pathway has emerged as a central hub that integrates the metabolism of sulfur-containing amino acids and redox homeostasis. Transsulfuration involves the transfer of sulfur from homocysteine to cysteine. Cysteine serves as the precursor for several sulfur-containing molecules, which play diverse roles in cellular processes.

Quantitative measurement of reactive oxygen species in mouse brain slices.

Evaluating redox homeostasis involves gauging the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) directly in tissues and cells. The brain is especially metabolically active and is particularly vulnerable to excessive ROS and RNS. Here, we describe a methodology to quantitatively measure ROS in mouse brain slices at baseline and after neural stimulation.

Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation.

Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD.

Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging.

Recognition of foreign or misplaced nucleic acids is one of the principal modes by which the immune system detects pathogenic entities. When cytosolic DNA is sensed, a signal is relayed via the cGAS-STING pathway: this involves the activation of cyclic GMP-AMP (cGMP-AMP) synthase (cGAS) and generation of the cyclic dinucleotide cGAMP, followed by the induction of stimulator of interferon genes (STING). The cGAS-STING pathway responds to viral, bacterial, and self-DNA.

Effects of hydrogen sulfide on mitochondrial function and cellular bioenergetics.

Hydrogen sulfide (HS) was once considered to have only toxic properties, until it was discovered to be an endogenous signaling molecule. The effects of HS are dose dependent, with lower concentrations being beneficial and higher concentrations, cytotoxic. This scenario is especially true for the effects of HS on mitochondrial function, where higher concentrations of the gasotransmitter inhibit the electron transport chain, and lower concentrations stimulate bioenergetics in multiple ways.