Sphingomyelin Inhibits Hydrolytic Activity of Heterodimeric PLA in Model Myelin Membranes: Pharmacological Relevance.

In this work, the heterodimeric phospholipase A, HDP-2, from viper venom was investigated for its hydrolytic activity in model myelin membranes as well as for its effects on intermembrane exchange of phospholipids (studied by phosphorescence quenching) and on phospholipid polymorphism (studied by H-NMR spectroscopy) to understand the role of sphingomyelin (SM) in the demyelination of nerve fibers. By using well-validated in vitro approaches, we show that the presence of SM in model myelin membranes leads to a significant inhibition of the hydrolytic activity of HDP-2, decreased intermembrane phospholipid exchange, and reduced phospholipid polymorphism. Using AutoDock software, we show that the NH group of the sphingosine backbone of SM binds to Tyr22(C=O) of HDP-2 via a hydrogen bond which keeps only the polar head of SM inside the HDP-2's active center and positions the sn-2 acyl ester bond away from the active center, thus making it unlikely to hydrolyze the alkyl chains at the sn-2 position.

Cobra Venom Cytotoxins as a Tool for Probing Mechanisms of Mitochondrial Energetics and Understanding Mitochondrial Membrane Structure.

In this paper, we provide an overview of mitochondrial bioenergetics and specific conditions that lead to the formation of non-bilayer structures in mitochondria. Secondly, we provide a brief overview on the structure/function of cytotoxins and how snake venom cytotoxins have contributed to increasing our understanding of ATP synthesis via oxidative phosphorylation in mitochondria, to reconcile some controversial aspects of the chemiosmotic theory. Specifically, we provide an emphasis on the biochemical contribution of delocalized and localized proton movement, involving direct transport of protons though the F unit of ATP synthase or via the hydrophobic environment at the center of the inner mitochondrial membrane (proton circuit) on oxidative phosphorylation, and how this influences the rate of ATP synthesis.

BDNF-TrkB Signaling in Mitochondria: Implications for Neurodegenerative Diseases.

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal development, synaptic plasticity, and overall neuronal health by binding to its receptor, tyrosine receptor kinase B (TrkB). This review delves into the intricate mechanisms through which BDNF-TrkB signaling influences mitochondrial function and potentially influences pathology in neurodegenerative diseases. This review highlights the BDNF-TrkB signaling pathway which regulates mitochondrial bioenergetics, biogenesis, and dynamics, mitochondrial processes vital for synaptic transmission and plasticity.

Brain-derived neurotrophic factor protects neurons by stimulating mitochondrial function through protein kinase A.

Brain-derived neurotrophic factor (BDNF) stimulates dendrite outgrowth and synaptic plasticity by activating downstream protein kinase A (PKA) signaling. Recently, BDNF has been shown to modulate mitochondrial respiration in isolated brain mitochondria, suggesting that BDNF can modulate mitochondrial physiology. However, the molecular mechanisms by which BDNF stimulates mitochondrial function in neurons remain to be elucidated.

Intranasal Administration of Forskolin and Noopept Reverses Parkinsonian Pathology in PINK1 Knockout Rats.

Parkinson's Disease (PD) is a brain-degenerative disorder characterized by a progressive loss of midbrain dopamine neurons. Current standard-of-care includes oral administration of Levodopa to address motor symptoms, but this treatment is not disease-modifying. A reduction in Protein Kinase A (PKA) signaling and neurotrophic support contributes to PD pathology.

Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease.

Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer's disease, Parkinson's disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain.

Evidence-based practice strategies for faculty professional development in clinical translational research at Institutional Development Award (IDeA) state institutions in the Mountain West.

The Mountain West Clinical Translational Research - Infrastructure Network (MW CTR-IN), established in 2013, is a research network of 13 university partners located among seven Institutional Development Award (IDeA) states targeting health disparities. This is an enormous undertaking because of the size of the infrastructure network (encompassing a third of the US landmass and spanning four time zones in predominantly rural and underserved areas, with populations that have major health disparities issues). In this paper, we apply the barriers, strategies, and metrics to an adapted educational conceptual model by Fink (2013).

Multiplexing Seahorse XF24 and ImageXpress Nano Platforms for Comprehensive Evaluation of Mitochondrial Bioenergetic Profile and Neuronal Morphology.

The measurement of mitochondrial function has become imperative to understand and characterize diseases characterized by bioenergetic alterations. The advancement of automation and application of high-throughput technologies has propelled our understanding of biological complexity and facilitated drug discovery. Seahorse extracellular flux (XF) technology measures changes in dissolved oxygen and proton concentration in cell culture media, providing kinetic measurements of oxidative phosphorylation and glycolytic metabolism.

Cardiolipin nanodisks confer protection against doxorubicin-induced mitochondrial dysfunction.

Doxorubicin (DOX) is an aqueous soluble anthracycline therapeutic widely used in cancer treatment. Although DOX anti-cancer activity is dose-dependent, increased dosage enhances the risk of cardiotoxicity. Despite intensive investigation, the molecular basis of this undesirable side effect has yet to be established.

Intraperitoneal Administration of Forskolin Reverses Motor Symptoms and Loss of Midbrain Dopamine Neurons in PINK1 Knockout Rats.

Background: Parkinson's disease (PD) is a relentless, chronic neurodegenerative disease characterized by the progressive loss of substantia nigra (SN) neurons that leads to the onset of motor and non-motor symptoms. Standard of care for PD consists of replenishing the loss of dopamine through oral administration of Levodopa; however, this treatment is not disease-modifying and often induces intolerable side effects. While the etiology that contributes to PD is largely unknown, emerging evidence in animal models suggests that a significant reduction in neuroprotective Protein Kinase A (PKA) signaling in the SN contributes to PD pathogenesis, suggesting that restoring PKA signaling in the midbrain may be a new anti-PD therapeutic alternative.

The Community of Bilingual English-Spanish Speakers Exploring Issues in Science and Health: Experiences During the COVID-19 Pandemic.

Language diversity is increasing in the United States. This growth has implications for language preference, cost, quality, and client outcomes in health services settings. However, language diversity among medical and allied health professionals is lacking.

Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: Implications for Parkinson's Disease.

Mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson's disease (PD). Consistent with this concept, loss of function mutations in the serine/threonine kinase- PINK1 (PTEN-induced putative kinase-1) causes autosomal recessive early onset PD. While the functional role of f-PINK1 (full-length PINK1) in clearing dysfunctional mitochondria via mitophagy is extensively documented, our understanding of specific physiological roles that the non-mitochondrial pool of PINK1 imparts in neurons is more limited.

Coenzyme Q nanodisks counteract the effect of statins on C2C12 myotubes.

Depletion of coenzyme Q (CoQ) is associated with disease, ranging from myopathy to heart failure. To induce a CoQ deficit, C2C12 myotubes were incubated with high dose simvastatin. This resulted in a concentration-dependent inhibition of cell viability.

Cleaved PINK1 induces neuronal plasticity through PKA-mediated BDNF functional regulation.

Mutations in PTEN-induced kinase 1 (PINK1) lead to early onset autosomal recessive Parkinson's disease in humans. In healthy neurons, full-length PINK1 (fPINK1) is post-translationally cleaved into different lower molecular weight forms, and cleaved PINK1 (cPINK1) gets shuttled to the cytosolic compartments to support extra-mitochondrial functions. While numerous studies have exemplified the role of mitochondrially localized PINK1 in modulating mitophagy in oxidatively stressed neurons, little is known regarding the physiological role of cPINK1 in healthy neurons.

Mitochondrial PKA Is Neuroprotective in a Cell Culture Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive decline. In hippocampal neurons, the pathological features of AD include the accumulation of extracellular amyloid-beta peptide (Aβ) accompanied by oxidative stress, mitochondrial dysfunction, and neuron loss. A decrease in neuroprotective Protein Kinase A (PKA) signaling contributes to mitochondrial fragmentation and neurodegeneration in AD.

Molecular Mechanism by which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane.

Cardiotoxin CTII from cobra venom translocates to the intermembrane space (IMS) of mitochondria to disrupt the structure and function of the inner mitochondrial membrane. At low concentrations, CTII facilitates ATP-synthase activity, presumably via the formation of non-bilayer, immobilized phospholipids that are critical in modulating ATP-synthase activity. In this study, we investigated the effects of another cardiotoxin CTI from cobra venom on the structure of mitochondrial membranes and on mitochondrial-derived ATP synthesis.

Psychological distress and lack of PINK1 promote bioenergetics alterations in peripheral blood mononuclear cells.

Psychological distress induces oxidative stress and alters mitochondrial metabolism in the nervous and immune systems. Psychological distress promotes alterations in brain metabolism and neurochemistry in wild-type (WT) rats in a similar manner as in Parkinsonian rats lacking endogenous PTEN-induced kinase 1 (PINK1), a serine/threonine kinase mutated in a recessive forms of Parkinson's disease. PINK1 has been extensively studied in the brain, but its physiological role in peripheral tissues and the extent to which it intersects with the neuroimmune axis is not clear.

Assembly and Characterization of Biocompatible Coenzyme Q -Enriched Lipid Nanoparticles.

Coenzyme Q (CoQ ) is a strongly hydrophobic lipid that functions in the electron transport chain and as an antioxidant. CoQ was conferred with aqueous solubility by incorporation into nanoparticles containing phosphatidylcholine (PtdCho) and apolipoprotein (apo) A-I. These particles, termed CoQ nanodisks (ND), contain 1.

Psychological Stress Phenocopies Brain Mitochondrial Dysfunction and Motor Deficits as Observed in a Parkinsonian Rat Model.

Psychological distress is a public health issue as it contributes to the development of human diseases including neuropathologies. Parkinson's disease (PD), a chronic, progressive neurodegenerative disorder, is caused by multiple factors including aging, mitochondrial dysfunction, and/or stressors. In PD, a substantial loss of substantia nigra (SN) neurons leads to rigid tremors, bradykinesia, and chronic fatigue.

A Pilot STEM Curriculum Designed to Teach High School Students Concepts in Biochemical Engineering and Pharmacology.

The creation of technology that affords for the design of artificial enzymes is a new branch of biochemical engineering with the objective to solve the looming global catastrophe including food shortages, energy crisis, novel diseases, climate change and environmental degradation. However, the development of science and technology that will lead to the design of artificial enzymes depends on availability of scientists with a broad range of expertise including chemistry and physics of chemical bonding, structural biochemistry of macromolecular interactions, theoretical physics and mathematics with the focus on computer modeling of dynamic docking of macromolecules. Our previous experience in university STEM education led us to conclude that in order to train future scientists with a broad expertise in STEM, it is critical for high school students to learn interdisciplinary concepts of STEM courses at an earlier age.

G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells.

G protein-coupled receptor kinase 2 (GRK2) is an important protein involved in β-adrenergic receptor desensitization. In addition, studies have shown GRK2 can modulate different metabolic processes in the cell. For instance, GRK2 has been recently shown to promote mitochondrial biogenesis and increase ATP production.

Cobra Cardiotoxin Targets Mitochondria to Disrupt Mitochondrial Membrane Structure and Function.

Cobra venom cardiotoxins (CVCs) can translocate to mitochondria to promote apoptosis by eliciting mitochondrial dysfunction. However, the molecular mechanism(s) by which CVCs are selectively targeted to the mitochondrion to disrupt mitochondrial function remains to be elucidated. By studying cardiotoxin from cobra (cardiotoxin VII4), a basic three-fingered S-type cardiotoxin, we hypothesized that cardiotoxin VII4 binds to cardiolipin (CL) in mitochondria to alter mitochondrial structure/function and promote neurotoxicity.

Neuroprotective Mitochondrial Remodeling by AKAP121/PKA Protects HT22 Cell from Glutamate-Induced Oxidative Stress.

Protein kinase A (PKA) is a ser/thr kinase that is critical for maintaining essential neuronal functions including mitochondrial homeostasis, bioenergetics, neuronal development, and neurotransmission. The endogenous pool of PKA is targeted to the mitochondrion by forming a complex with the mitochondrial scaffold A-kinase anchoring protein 121 (AKAP121). Enhanced PKA signaling via AKAP121 leads to PKA-mediated phosphorylation of the fission modulator Drp1, leading to enhanced mitochondrial networks and thereby blocking apoptosis against different toxic insults.