Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells.

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells.

Publication date: Nov 05, 2019

Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.

Anderson, G., Rodriguez, M., and Reiter, R.J. Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells. 19434. 2019 Int J Mol Sci (20):21.

Concepts Keywords
Acetyl Branches of biology
Acetyl CoA Acetamides
Air Pollutants Antioxidants
Aryl Hydrocarbon Receptor Circadian rhythm
Butyrate Melatonin receptor agonists
Ceramide Mitochondria
Circadian Mitochondrion
CoA Gut flora
Coagulation Butyrate
Coenzyme Orexin
Cytochrome P450 HMGB1
Disinhibition
Glia
Gut Permeability
Immune Cells
Interact
Kynurenine
Lipopolysaccharide
LPS
Melatonergic
Melatonin
Microbiome
Mitochondria
Mitochondrial
Modulation
Multiple Sclerosis
Nitric Oxide Synthase
Orexin
Oxidative Phosphorylation
Pathophysiology
Permeability
Peroxynitrite
Platelet
Progressive
Pyruvate Dehydrogenase Complex
Receptor
Sci
Sphingomyelinase
Stress
Substrate
Superoxide
TLR

Semantics

Type Source Name
disease MESH Multiple Sclerosis
disease DOID Multiple Sclerosis
drug DRUGBANK Melatonin
gene UNIPROT HCRT
pathway BSID Platelet activation
drug DRUGBANK Butyric Acid
disease MESH Circadian Dysregulation
gene UNIPROT HMGB1
drug DRUGBANK Nitric Oxide
disease MESH dysbiosis
pathway BSID Oxidative phosphorylation
drug DRUGBANK Coenzyme A
pathway BSID Aryl Hydrocarbon Receptor
gene UNIPROT AHR
drug DRUGBANK Medical air
drug DRUGBANK N-acetylserotonin
disease MESH inflammation

Original Article

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