Nutrition as a systems regulator of brain aging trajectories.

The blood-brain barrier is an interface between the circulation and brain. It is responsible for the homeostasis of central nervous system, protection and feeding of the brain and for providing the conditions for fine regulation of neurons. The coordinated function of different cell types and the regulated expression of molecular systems make possible the functionality of blood-brain barrier. However, this complex system can be broken due to different insults with a consequence of appearance of elevated levels of unwanted exogenous and endogenous molecules in the brain involved in the pathomechanisms of several disorders. The most important risk factor for the damage of blood-brain barrier is the aging itself, which causes disruption of the barrier through DNA mutation, oxidative stress and release of inflammatory mediators. Although the physiological aging is accompanied by morphological changes, the dysfunction of membrane transporters could also lead to neurodegenerative disorders. Structure, function and breakdown of the blood-brain barrier and the possibilities to cross it, are presented. Orv. Hetil., 2016, 157(51), 2019-2027.

The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood. We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM. Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific Pgam5 knockout (Pgam5cKO) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, Pgam5 depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2S91D) and phospho-defective (Phb2S9A) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing Phb2S91D were resistant to alcohol-induced heart dysfunction. We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2S91 dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice. Pgam5 knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice. Pgam5 KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice. Pgam5 depletion protects mitochondrial function in alcohol-exposed male mouse cardiomyocytes. Pgam5 depletion normalises MQC in ACM. EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91. Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation. Transgenic mice expressing a Ser91 phospho-mimetic Phb2 mutant are resistant to ACM.

Mitochondria are central regulators of cellular energy production, metabolic homeostasis, and stress responses, and their dysfunction represents a critical hallmark of neurodegenerative and neuroinflammatory diseases. To preserve mitochondrial integrity, cells rely on an intricate mitochondrial quality control system encompassing mitochondrial dynamics, mitophagy, biogenesis, and vesicle-mediated pathways. Emerging evidence highlights the pivotal role of mitochondria-derived vesicles as vehicles for trafficking mitochondrial components within cells, thereby contributing significantly to intracellular communication and mitochondrial quality control. In parallel, mitochondrial extracellular vesicles have been identified as dynamic mediators of intercellular communication, enabling the transfer of mitochondrial proteins, lipids, and even mitochondrial DNA between cells. Mitochondria-derived vesicles selectively remove damaged mitochondrial components and coordinate intracellular stress responses, whereas mitochondrial extracellular vesicles can transfer mitochondrial material, including proteins, mitochondrial DNA, and even intact mitochondria, between cells, thereby modulating inflammation, immune activation, and cellular bioenergetics. Interestingly, mitochondrial extracellular vesicles play a dual, context-dependent role: they can exacerbate pathology when carrying damaged or dysfunctional mitochondrial cargo, or promote cellular resilience when delivering healthy, functional mitochondrial components. Likewise, extracellular vesicles derived from mesenchymal stem cells, including larger extracellular vesicle populations capable of transferring functional mitochondria, are emerging as promising cell-free therapeutic candidates with the potential to restore mitochondrial function and promote tissue repair across multiple diseases, including neurodegenerative disorders. Collectively, these insights establish mitochondrial vesicular trafficking as a transformative frontier for diagnostic innovation, biomarker development, and novel therapeutic strategies in neurodegenerative and mitochondria-related central nervous system disorders. Implications for the field include: the recognition of mitochondrial vesicular pathways as fundamental regulators of central nervous system homeostasis highlights their crucial roles in sustaining neuronal function, cellular resilience, and overall brain health. When enriched with dysfunctional mitochondrial cargo, mitochondrial extracellular vesicles are emerging as key contributors to the etiopathogenesis of neurodegenerative and neuroinflammatory diseases, thereby driving disease initiation and progression. In parallel, their ability to reflect mitochondrial status positions mitochondrial extracellular vesicles - particularly those containing mitochondrial DNA and mitochondrial proteins - as promising biomarkers for monitoring mitochondrial stress, disease activity, and therapeutic response. At the translational level, advancing mitochondrial extracellular vesicles and mitochondrial vesicular pathways as therapeutic tools opens new opportunities to restore mitochondrial integrity, modulate neuroinflammation, and potentially modify disease trajectories. The objectives of this review are to: (1) delineate the mechanisms of mitochondrial dysfunction and mitochondrial quality control failure in neurodegenerative and neuroinflammatory diseases; (2) comprehensively characterize the biogenesis, trafficking pathways, and functional roles of mitochondria-derived vesicles; (3) evaluate experimental and clinical evidence supporting the role of mitochondrial extracellular vesicles as mediators of neuroimmune communication and mitochondrial transfer; (4) critically assess the therapeutic potential of mesenchymal stem cell-derived mitochondrial extracellular vesicles.

Rescuers from the Other Shore: Intercellular Mitochondrial Transfer and Its Implications in Central Nervous System Injury and Diseases.

BackgroundThe Blood Brain Barrier (BBB) maintains the homeostasis of central nervous system by preventing the free passage of macromolecules from the systemic circulation into the brain. This normal physiological function of the BBB presents a challenge for delivery of therapeutic compounds into the brain. Recent studies have shown that the application of focused ultrasound together with ultrasound contrast agent (microbubbles) temporarily increases the permeability of the BBB. This effect is associated with breakdown of tight junctions, the structures that regulate the paracellular permeability of the endothelial cell layer. The influence of this ultrasound effect on the activation of intracellular signaling proteins is currently not well understood. Therefore, the aim of this study was to investigate the activation of cell survival signaling molecules in response to ultrasound-mediated BBB opening;MethodsThe BBB was disrupted in two four-spot lines (1-1.5 mm spacing) along the right hemisphere of rat brain with ultrasound beams (0.3 MPa, 120 s, 10 ms bursts, repetition frequency = 1 Hz) in the presence Definity microbubbles. Contrast-enhanced MRI images were acquired to assess the extent of BBB opening upon which the animals were sacrificed and the brains removed and processed for biochemical and immunohistochemical analyses;ResultsImmunoblotting of sonicated brain lysates resolved by SDS-PAGE demonstrated an increase in phosphorylation of Akt and its downstream signaling molecule, GSK3β, while the phosphorylation of MAPK remained unchanged. The elevated levels of pAkt and pGSK3β are still evident after 24 hours post-sonication, a time point where the integrity of the BBB is known to be re-established. Furthermore, immunofluoresence staining localized this increase in pAkt and pGSK3β levels to neuronal cells flanking the region of the disrupted BBB;ConclusionsOur data demonstrates that ultrasound-mediated BBB disruption causes an activation of the Akt signaling pathway in neuronal cells surrounding the disrupted BBB.

Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-β1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis. Here, we analyzed the effect of a decrease in TGF-β1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-β1 antibody (anti-TGF-β1; 1 mg/mL). Next, we correlated it with a thrombocytopenia-induced TGF-β1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-β1 decrease on blood–brain barrier functionality. The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins’ decrease in analyzed fractions occurred in anti-TGF-β1 mice. In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-β mice, was observed. The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-β1 model. The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-β1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice.

In this study, we examined the effect of lambda-carrageenan-induced inflammatory pain on the functional and structural properties of the rat blood-brain barrier (BBB) over a 72-h time period. Systemic inflammation was induced by an intraplantar injection of 3% lambda-carrageenan into the right hind paw of female Sprague-Dawley rats. In situ brain perfusion and Western blot analyses were performed at 1, 3, 6, 12, 24, 48, and 72 h. In situ brain perfusion showed lambda-carrageenan significantly increased brain uptake of [(14)C]sucrose at 1, 3, 6, and 48 h (139 +/- 9%, 166 +/- 19%, 138 +/- 13%, and 146 +/- 7% compared with control, respectively). Capillary depletion analysis insured the increased brain uptake was due to increased BBB permeability and not vascular trapping. Western blot analyses for zonula occludens-1 (ZO-1) and occludin were performed on isolated cerebral microvessels. ZO-1 expression was significantly increased at 1, 3, and 6 h and returned to control expression levels by 12 h. Total occludin expression was significantly reduced at 1, 3, 6, 12, and 48 h. This investigation demonstrated that lambda-carrageenan-induced inflammatory pain elicits a biphasic increase in BBB permeability with the first phase occurring from 1-6 h and the second phase occuring at 48 h. Furthermore, changes in BBB function are correlated with altered tight junctional protein expression of occludin and ZO-1. Changes in the structure of tight junctions may have important clinical ramifications concerning central nervous system homeostasis and therapeutic drug delivery.

Targeting mitochondrial quality control for myocardial ischemia-reperfusion injury.

The brain is an immune-privileged organ such that immune cell infiltration is highly regulated and better tolerating the introduction of antigen to reduce risk of harmful inflammation. Thus, the composition and the nature of the immune response is fundamentally different in the brain where avoiding immunopathology is prioritized compared to other peripheral organs. While the principle of immune privilege in the central nervous system (CNS) still holds true, the role of the immune system in the CNS has been revisited over the recent years. This redefining of immune privilege in the brain is a result of the recent re-discovery of the extensive CNS meningeal lymphatic system and the identification of resident T cells in the brain, meningeal layers, and its surrounding cerebrospinal fluid (CSF) in both humans and rodents. While neuro-immune interactions have been classically studied in the context of neuroinflammatory disease, recent works have also elucidated unconventional roles of immune-derived cytokines in neurological function, highlighting the many implications and potential of neuro-immune interactions. As a result, the study of neuro-immune interactions is becoming increasingly important in understanding both CNS homeostasis and disease. Here, we review the anatomically distinct immune compartments within the brain, the known mechanisms of leukocyte trafficking and infiltration into the CNS and unique transcriptional and functional characteristics of CNS-resident immune cells.

The blood-brain barrier (BBB) actually consists of several relatively distinct barriers, operating in parallel to one another in different anatomical regions. These barriers restrict and regulate the passage of materials between the peripheral and cerebrospinal compartments. The best studied and most important of the barriers are the vascular barrier and the choroid plexus. Barrier functions arises through mechanisms associated primarily with endothelial cells (tight junctions, infrequent fenestrations, reduced pinocytosis) but also involve the capillary basement membrane, pericytes, and astrocytes. BBB function responds dynamically to the needs of the central nervous system (CNS) and for this reason the BBB is sometimes described as a "slave" of the CNS. The BBB communicates with microglia, neurons, and other cells, and it responds to a wide range of soluble factors released by these cells. Multiple transport processes, both passive and active, carry materials into and out of (efflux) the cerebrospinal fluid. Efflux mechanisms help explain why some drugs fail to reach therapeutic concentrations in the CNS; and inter-individual variations in efflux mechanisms can explain why some people are more or less sensitive to the therapeutic effects or side effects of particular CNS medications. Immune cells, once thought to be excluded from the CNS except under conditions of brain infection, are now recognized to patrol the normal CNS; and a major type of brain cell, the microglia, is derived from peripheral macrophages and may exist in some (as-yet poorly defined) equilibrium with the peripheral macrophage pool. This chapter presents these varied aspects of BBB structure and function in some detail, then builds on that fundamental understanding to discuss the BBB's role in neuroimmune interactions in both health and disease, including in HIV-1 disease.

Recently, a rising interest is given to neuroimmune communication in physiological and neuropathological conditions. Meningeal immunity is a complex immune environment housing different types of immune cells. Here, we focus on meningeal T cells, possibly the most explored aspect of neuro-immune cell interactions. Emerging data have shown that meningeal T cells play a crucial role in the pathogenesis of several neurodegenerative disorders, including multiple sclerosis, Alzheimer's, Parkinson's, and Huntington's diseases. This review highlights how meningeal T cells may contribute to immune surveillance of the central nervous system (CNS) and regulate neurobehavioral functions through the secretion of cytokines. Overall, this review assesses the recent knowledge of meningeal T cells and their effects on CNS functioning in both health and disease conditions and the underlying mechanisms.

Mitochondria lie at the crossroads of neuronal survival and cell death. They play important roles in cellular bioenergetics, control intracellular Ca2+ homeostasis, and participate in key metabolic pathways. Mutations in genes involved in mitochondrial quality control cause a myriad of neurodegenerative diseases. Mitochondria have evolved strategies to kill cells when they are not able to continue their vital functions. This review provides an overview of the role of mitochondria in neurologic disease and the cell death pathways that are mediated through mitochondria, including their role in accidental cell death, the regulated cell death pathways of apoptosis and parthanatos, and programmed cell death. It details the current state of parthanatic cell death and discusses potential therapeutic strategies targeting initiators and effectors of mitochondrial-mediated cell death in neurologic disorders.

Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons

It is now becoming clear that human metabolism is extremely plastic and varies substantially between healthy individuals. Understanding the biochemistry that underlies this physiology will enable personalized clinical interventions related to metabolism. Mitochondrial quality control and the detailed mechanisms of mitochondrial energy generation are central to understanding susceptibility to pathologies associated with aging including cancer, cardiac and neurodegenerative diseases. A precision medicine approach is also needed to evaluate the impact of exercise or caloric restriction on health. In this review, we discuss how technical advances in assessing mitochondrial genetics, cellular bioenergetics and metabolomics offer new insights into developing metabolism-based clinical tests and metabolotherapies. We discuss informatics approaches, which can define the bioenergetic-metabolite interactome and how this can help define healthy energetics. We propose that a personalized medicine approach that integrates metabolism and bioenergetics with physiologic parameters is central for understanding the pathophysiology of diseases with a metabolic etiology. New approaches that measure energetics and metabolomics from cells isolated from human blood or tissues can be of diagnostic and prognostic value to precision medicine. This is particularly significant with the development of new metabolotherapies, such as mitochondrial transplantation, which could help treat complex metabolic diseases.

Bioenergetic dysfunction is emerging as a cornerstone for establishing a framework for understanding the pathophysiology of cardiovascular disease, diabetes,cancer and neurodegeneration. Recent advances in cellular bioenergetics have shown that many cells maintain a substantial bioenergetic reserve capacity, which is a prospective index of ‘ healthy ’ mitochondrial populations.The bioenergetics of the cell are likely regulated by energy requirements and substrate availability. Additionally,the overall quality of the mitochondrial population and the relative abundance of mitochondria in cells and tissues also impinge on overall bioenergetic capacity and resistance to stress. Because mitochondria are susceptible to damage mediated by reactive oxygen/nitrogen and lipid species, maintaining a ‘ healthy ’ population of mitochondria through quality control mechanisms appears to be essential for cell survival under conditions of pathological stress. Accumulating evidence suggest that mitophagy is particularly important for preventing amplification of initial oxidative insults, which otherwise would further impair the respiratory chain or promote mutations in mitochondrial DNA (mtDNA). The processes underlying the regulation of mitophagy depend on several factors, including the integrity of mtDNA, electron transport chain activity, and the interaction and regulation of the autophagic machinery. The integration and interpretation of cellular bioenergetics in the context of mitochondrial quality control and genetics is the theme of this review.