Mitochondrial Energy Generation Research Articles

Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy

Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.

HIF‐1α Affects Sperm Autophagy and Motility

Male infertility is frequently caused by decreased sperm motility. Sperm of low progressive motility showed abnormal energy metabolism and elevated autophagy rate, although the specific mechanisms remain elusive. Hypoxia‐inducible factor 1α (HIF‐1α) is a transcription factor activated by hypoxia and plays a crucial role in regulating biological oxygen homeostasis. Negative correlation between sperm motility and HIF‐1α expression and a potential association with the PI3K/Akt/mTOR signaling pathway were observed. To further explore the mechanisms by which HIF‐1α impacts sperm motility, normal human sperm were treated with cobalt chloride (CoCl2) or YC‐1. Sperm autophagy rate, ATP production, levels of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and HIF‐1α, p‐AKT, p‐mTOR, and LC3B were assessed. The results showed that CoCl2 or YC‐1 decreased sperm motility and increased sperm autophagy rate. The levels of intracellular ROS, HIF‐1α, p‐AKT, p‐mTOR, and LC3B were significantly increased, while the levels of sperm ATP and MMP reduced. These findings suggested that HIF‐1α might affect mitochondrial structure and energy generation, leading to increased autophagy rate and decreased motility in human sperm, with the PI3K/Akt/mTOR pathway potentially playing a role in this process by exerting an inhibitory effect on autophagy.

Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission.

Fibroblast activation and proliferation is an essential phase in the progression of renal fibrosis. Despite the recognized significance of glutamine metabolism in cellular growth and proliferation, its precise pathophysiological relevance in renal fibrosis remains uncertain. Therefore, this study aims to investigate the involvement of glutamine metabolism in fibroblast activation and its possible mechanism. Our findings highlight the importance of glutamine metabolism in fibroblast activation and reveal that patients with severe fibrosis exhibit elevated serum glutamine levels and increased expression of kidney glutamine synthetase. Furthermore, the deprivation of glutamine metabolism in vitro and in vivo could inhibit fibroblast activation, thereby ameliorating renal fibrosis. It was also detected that glutamine metabolism is crucial for maintaining mitochondrial function and morphology. These effects may partially depend on the metabolic intermediate α-ketoglutaric acid. Moreover, glutamine deprivation led to upregulated mitochondrial fission in fibroblasts and the activation of the mammalian target of rapamycin / mitochondrial fission process 1 / dynamin-related protein 1 pathway. Thus, these results provide compelling evidence that the modulation of glutamine metabolism initiates the regulation of mitochondrial function, thereby facilitating the progression of renal fibrosis. Consequently, targeting glutamine metabolism emerges as a novel and promising avenue for therapeutic intervention and prevention of renal fibrosis.

Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation

BackgroundViral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervous system (CNS) metabolism than autoimmune processes and searched for metabolite biomarkers in cerebrospinal fluid (CSF) to distinguish between the two conditions.MethodsWe applied a targeted metabolomic/lipidomic analysis to CSF samples from patients with viral CNS infections (n = 34; due to herpes simplex virus [n = 9], varicella zoster virus [n = 15], enteroviruses [n = 10]), autoimmune neuroinflammation (n = 25; autoimmune anti-NMDA-receptor encephalitis [n = 8], multiple sclerosis [n = 17), and non-inflamed controls (n = 31; Gilles de la Tourette syndrome [n = 20], Bell’s palsy with normal CSF cell count [n = 11]). 85 metabolites passed quality screening and were evaluated as biomarkers. Standard diagnostic CSF parameters were assessed for comparison.ResultsOf the standard CSF parameters, the best biomarkers were: CSF cell count for viral infections vs. controls (area under the ROC curve, AUC = 0.93), Q-albumin for viral infections vs. autoimmune neuroinflammation (AUC = 0.86), and IgG index for autoimmune neuroinflammation vs. controls (AUC = 0.90). Concentrations of 2 metabolites differed significantly (p < 0.05) between autoimmune neuroinflammation and controls, with proline being the best biomarker (AUC = 0.77). In contrast, concentrations of 67 metabolites were significantly higher in viral infections than controls, with SM.C16.0 being the best biomarker (AUC = 0.94). Concentrations of 68 metabolites were significantly higher in viral infections than in autoimmune neuroinflammation, and the 10 most accurate metabolite biomarkers (AUC = 0.89–0.93) were substantially better than Q-albumin (AUC = 0.86). These biomarkers comprised six phosphatidylcholines (AUC = 0.89–0.92), two sphingomyelins (AUC = 0.89, 0.91), and acylcarnitines isobutyrylcarnitine (C4, AUC = 0.92) and isovalerylcarnitine (C5, AUC = 0.93). Elevated C4 and C5 concentrations suggested dysfunctional mitochondrial β-oxidation and correlated only moderately with CSF cell count (Spearman ρ = 0.41 and 0.44), indicating that their increase is not primarily driven by inflammation.ConclusionsChanges in CNS metabolism differ substantially between viral CNS infections and autoimmune neuroinflammation and reveal CSF metabolites as pathophysiologically relevant diagnostic biomarkers for the differentiation between the two conditions. In viral CNS infections, the observed higher concentrations of free phospholipids are consistent with disruption of host cell membranes, whereas the elevated short-chain acylcarnitines likely reflect compromised mitochondrial homeostasis and energy generation.

A clinical study and future prospects for bioactive compounds and semi-synthetic molecules in the therapies for Huntington's disease.

A neurodegenerative disorder (ND) refersto Huntington's disease (HD) whichaffects memory loss, weight loss, and movement dysfunctions such as chorea and dystonia. In the striatum and brain, HD most typically impacts medium-spiny neurons. Molecular genetics, excitotoxicity, oxidative stress (OS), mitochondrial, and metabolic dysfunction are a few of the theories advanced to explicit the pathophysiology of neuronal damage and cell death. Numerous in-depth studies of the literature have supported the therapeutic advantages of natural products in HD experimental models and other treatment approaches. This article briefly discusses the neuroprotective impacts of natural compounds against HD models. The ability of the discovered natural compounds to suppress HD was tested using either in vitro or in vivo models. Many bioactive compounds considerably lessened the memory loss and motor coordination brought on by 3-nitropropionic acid (3-NP). Reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and enhanced mitochondrial energy generation have profoundly decreased the biochemical change. It is significant since histology showed that therapy with particular natural compounds lessened damage to the striatum caused by 3-NP. Moreover, natural products displayed varyingdegrees of neuroprotection in preclinical HD studies because of their antioxidantand anti-inflammatory properties, maintenance of mitochondrial function, activation of autophagy,and inhibition of apoptosis. This study highlighted about the importance of bioactive compounds and their semi-synthetic molecules in the treatment and prevention of HD.

Chronic Ambient Ozone Exposure Aggravates Autism-Like Symptoms in a Susceptible Mouse Model.

Although there is evidence that exposure to ground-level ozone (O3) may cause an increased risk of neurological disorders (e.g., autistic spectrum disorder), low-dose chronic ozone exposure and its adverse effects on the nervous system have not been fully understood. Here, we evaluated the potential neurotoxic effects of long-term exposure to environmentally relevant O3 concentration (200 μg/m3 via a whole-body inhalation system, 12 h/day for 5 days/week) using a susceptible mouse model of autism induced by valproic acid. Various indicators of oxidative stress, mitochondria, and synapse in the brain tissues were then measured to determine the overall damage of O3 to the mouse brain. The results showed an aggravated risk of autism in mice offspring, which was embodied in decreased antioxidant contents, disturbed energy generation in mitochondria, as well as reduced expressions of protein kinase Mζ (PKMζ) and synaptic proteins [e.g., Synapsin 1 (SYN 1), postsynaptic density protein-95 (PSD-95)]. Overall, our study indicates that prenatal exposure to environmentally relevant O3 may exacerbate the symptoms of autism, shedding light on possible molecular mechanisms and providing valuable insights into the pathogenesis of autism, especially concerning low-dose levels of those pollutants.

Meldonium Inhibits Cell Motility and Wound-Healing in Trabecular Meshwork Cells and Scleral Fibroblasts: Possible Applications in Glaucoma.

Meldonium (MID) is a synthetic drug designed to decrease the availability of L-carnitine-a main player in mitochondrial energy generation-thus modulating the cell pathways of energy metabolism. Its clinical effects are mostly evident in blood vessels during ischemic events, when the hyperproduction of endogenous carnitine enhances cell metabolic activities, leading to increased oxidative stress and apoptosis. MID has shown vaso-protective effects in model systems of endothelial dysfunction induced by high glucose or by hypertension. By stimulating the endothelial nitric oxide synthetase (eNOS) via PI3 and Akt kinase, it has shown beneficial effects on the microcirculation and blood perfusion. Elevated intraocular pressure (IOP) and endothelial dysfunction are major risk factors for glaucoma development and progression, and IOP remains the main target for its pharmacological treatment. IOP is maintained through the filtration efficiency of the trabecular meshwork (TM), a porous tissue derived from the neuroectoderm. Therefore, given the effects of MID on blood vessels and endothelial cells, we investigated the effects of the topical instillation of MID eye drops on the IOP of normotensive rats and on the cell metabolism and motility of human TM cells in vitro. Results show a significant dose-dependent decrease in the IOP upon topic treatment and a decrease in TM cell motility in the wound-healing assay, correlating with an enhanced expression of vinculin localized in focal adhesion plaques. Motility inhibition was also evident on scleral fibroblasts in vitro. These results may encourage a further exploration of MID eye drops in glaucoma treatment.

Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins.

To address the mechanistic pathways focusing on mitochondria dysfunction, oxidative stress, sirtuins imbalance, and other contributors in patient with metabolic syndrome and cardiovascular disease. Sodium glucose co-transporter type 2 (SGLT-2) inhibitors deeply influence these mechanisms. Recent randomized clinical trials have shown impressive results in improving cardiac function and reducing cardiovascular and renal events. These unexpected results generate the need to deepen our understanding of the molecular mechanisms able to generate these effects to help explain such significant clinical outcomes. Cardiovascular disease is highly prevalent among individuals with metabolic syndrome and diabetes. Furthermore, mitochondrial dysfunction is a principal player in its development and persistence, including the consequent cardiac remodeling and events. Another central protagonist is the renin-angiotensin system; the high angiotensin II (Ang II) activity fuel oxidative stress and local inflammatory responses. Additionally, sirtuins decline plays a pivotal role in the process; they enhance oxidative stress by regulating adaptive responses to the cellular environment and interacting with Ang II in many circumstances, including cardiac and vascular remodeling, inflammation, and fibrosis. Fasting and lower mitochondrial energy generation are conditions that substantially reduce most of the mentioned cardiometabolic syndrome disarrangements. In addition, it increases sirtuins levels, and adenosine monophosphate-activated protein kinase (AMPK) signaling stimulates hypoxia-inducible factor-1β (HIF-1 beta) and favors ketosis. All these effects favor autophagy and mitophagy, clean the cardiac cells with damaged organelles, and reduce oxidative stress and inflammatory response, giving cardiac tissue protection. In this sense, SGLT-2 inhibitors enhance the level of at least four sirtuins, some located in the mitochondria. Moreover, late evidence shows that SLGT-2 inhibitors mimic this protective process, improving mitochondria function, oxidative stress, and inflammation. Considering the previously described protection at the cardiovascular level is necessary to go deeper in the knowledge of the effects of SGLT-2 inhibitors on the mitochondria function. Various of the protective effects these drugs clearly had shown in the trials, and we briefly describe it could depend on sirtuins enhance activity, oxidative stress reduction, inflammatory process attenuation, less interstitial fibrosis, and a consequent better cardiac function. This information could encourage investigating new therapeutic strategies for metabolic syndrome, diabetes, heart and renal failure, and other diseases.

Human ApoE2 Endows Stronger Contractility in Rat Cardiomyocytes Enhancing Heart Function

(1) Background: Apolipoprotein E (ApoE) is a critical plasma apolipoprotein for lipid transport and nonlipid-related functions. Humans possess three isoforms of ApoE (2, 3, and 4). ApoE2, which exhibits beneficial effects on cardiac health, has not been adequately studied. (2) Methods: We investigated the cardiac phenotypes of the humanized ApoE knock-in (hApoE KI) rats and compared to wild-type (WT) and ApoE knock-out (ApoE KO) rats using echocardiography, ultrasound, blood pressure measurements, histology strategies, cell culture, Seahorse XF, cardiomyocyte contractility and intracellular Ca2+ tests, and Western blotting; (3) Results: hApoE2 rats exhibited enhanced heart contractile function without signs of detrimental remodeling. Isolated adult hApoE2 cardiomyocytes had faster and stronger sarcomere contractility because of more mitochondrial energy generation and stimulation-induced fast and elevated intracellular Ca2+ transient. The abundant energy is a result of elevated mitochondrial function via fatty acid β-oxidation. The fast and elevated Ca2+ transient is associated with decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2) and increased expression of cardiac ryanodine receptor 2 (RyR2) conducting a potent Ca2+ release from SR.; (4) Conclusions: Our studies validated the association of polymorphic ApoEs with cardiac health in the rat model, and revealed the possible mechanisms of the protective effect of ApoE2 against heart diseases.

Label-free and non-destructive identification of naïve and primed embryonic stem cells based on differences in cellular metabolism

Pluripotent stem cells (PSCs) exist in naïve or primed states based on their origin. For in vitro culture, these PSCs require different supplements and growth factors. However, owing to their similar phenotypic features, identifying both cell types without harming cellular functions is challenging. This study reports an electrochemical method that enables simple, label-free, and non-destructive detection of naïve embryonic stem cells (ESCs) derived from mouse ESCs, based on the differences in cellular metabolism. Two major metabolic pathways to generate adenosine triphosphate (ATP)—glycolysis and oxidative phosphorylation (OXPHOS)—were blocked, and it was found that mitochondrial energy generation is the origin of the strong electrochemical signals of naïve ESCs. The number of ESCs is quantified when mixed with primed ESCs or converted from naïve–primed switchable metastable ESCs. The mouse PSCs derived from doxycycline-inducible mouse embryonic fibroblasts (MEFs) are also sensitively identified among other cell types such as unconverted MEFs and primed PSCs. The developed sensing platform operates in a non-invasive and label-free manner. Thus, it can be useful in the development of stem cell-derived therapeutics.

Mitochondrial biology and dysfunction in secondary mitochondrial disease.

Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary mitochondrial disease (PMD) defines pathologies resulting from mutation of mitochondrial DNA (mtDNA) or nuclear genes affecting either mtDNA expression or the biogenesis and function of the respiratory chain. Secondary mitochondrial disease (SMD) arises due to mutation of nuclear-encoded genes independent of, or indirectly influencing OXPHOS assembly and operation. Despite instances of novel SMD increasing year-on-year, PMD is much more widely discussed in the literature. Indeed, since the implementation of next generation sequencing (NGS) techniques in 2010, many novel mitochondrial disease genes have been identified, approximately half of which are linked to SMD. This review will consolidate existing knowledge of SMDs and outline discrete categories within which to better understand the diversity of SMD phenotypes. By providing context to the biochemical and molecular pathways perturbed in SMD, we hope to further demonstrate the intricacies of SMD pathologies outside of their indirect contribution to mitochondrial energy generation.

What Causes ME/CFS: The Role of the Dysfunctional Immune System and Viral Infections

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigmatic highly disabling and complex long-term condition with a wide range of aetiologies and symptoms. A viral onset is commonly mentioned by patients and several bodily systems are ultimately disturbed. The parallel with long-covid is clear. However, immune dysregulation with impaired NK cell dysfunction and tendency to novel autoimmunity have been frequently reported. These may contribute to reactivation of previous acquired viruses/retrovirusesaccompanied by impaired endocrine regulation and mitochondrial energy generation. The unpredictable nature of seemingly unconnected and diverse symptoms that are poorly responsive to several allopathic and alternative therapies then contributes to an escalation of the illness with secondary dysfunction of multiple other systems. Treatment of established ME/CFS is therefore difficult and requires multi-specialty input addressing each of the areas affected by the illness.

HYPERTRICHOSIS ASSOCIATED WITH GENETIC CONDITIONS WITH HEAD AND NECK CHANGES

<h3>Objectives</h3> Evaluate the presence of congenital hypertrichosis associated with genetic syndromes and conditions that affect the head and neck. <h3>Study Design</h3> The search was carried out in the PubMed-NCBI databases, Online Mendelian Inheritance in Man, and Protein. The descriptor "hypertrichosis" was used with limitation to English literature. <h3>Results</h3> The analysis was performed on 63 articles. Hypertrichosis, when commonly found together with craniofacial involvement, was related to its generalized form. In the syndromes, a prevalence of autosomal dominant inheritance was seen in 48.64% of cases, autosomal recessive in 45.9%, as well as 1 X-linked recessive case and 1 due to defective mitochondrial energy generation. Forty-four were accompanied by neurodevelopmental changes. Besides the craniofacial involvement itself, there is a high prevalence of alterations of the oral structures involving the 47 teeth of all conditions. <h3>Conclusions</h3> The clinical evaluation of the maxillomandibular complex that the dentist routinely performs is extremely important to help detect genetic conditions that have craniofacial involvement. In case of suspicion, it is necessary to refer the patient to a physician for evaluation of the patient's systemic condition, consequently improving the oral clinical outcome and a better conduct.

Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus.

Nucleic acid autoantibodies, increase type I interferon (IFN-α) levels, and immune cell hyperactivation are hallmarks of systemic lupus erythematosus (SLE). Notably, immune cell activation requires high level of cellular energy that is predominately generated by the mitochondria. Mitochondrial reactive oxygen species (mROS), the byproduct of mitochondrial energy generation, serves as an essential mediator to control the activation and differentiation of cells and regulate the antigenicity of oxidized nucleoids within the mitochondria. Recently, clinical trials on normalization of mitochondrial redox imbalance by mROS scavengers and those investigating the recovery of defective mitophagy have provided novel insights into SLE prophylaxis and therapy. However, the precise mechanism underlying the role of oxidative stress-related mitochondrial molecules in skewing the cell fate at the molecular level remains unclear. This review outlines distinctive mitochondrial functions and pathways that are involved in immune responses and systematically delineates how mitochondrial dysfunction contributes to SLE pathogenesis. In addition, we provide a comprehensive overview of damaged mitochondrial function and impaired metabolic pathways in adaptive and innate immune cells and lupus-induced organ tissues. Furthermore, we summarize the potential of current mitochondria-targeting drugs for SLE treatment. Developing novel therapeutic approaches to regulate mitochondrial oxidative stress is a promising endeavor in the search for effective treatments for systemic autoimmune diseases, particularly SLE.

Physiological and Pathophysiological Roles of Thioredoxin Interacting Protein: A Perspective on Redox Inflammation and Metabolism.

Significance: Thioredoxin interacting protein (TXNIP) is a member of the arrestin fold superfamily with important cellular functions, including cellular transport, mitochondrial energy generation, and protein cycling. It is the only arrestin-domain protein known to covalently bind to thioredoxin and plays roles in glucose metabolism, inflammation, apoptosis, and cancer. Recent Advances: The crystal structure of the TXNIP-thioredoxin complex provided details about this fascinating interaction. Recent studies showed that TXNIP is induced by endoplasmic reticulum (ER) stress, activates NLR family pyrin domain containing 3 (NLRP3) inflammasomes, and can regulate glucose transport into cells. The tumor suppressor role of TXNIP in various cancer types and the role of TXNIP in fructose absorption are now described. Critical Issues: The influence of TXNIP on redox state is more complex than its interaction with thioredoxin. Future Directions: It is incompletely understood which functions of TXNIP are thioredoxin-dependent. It is also unclear whether TXNIP binding can inhibit glucose transporters without endocytosis. TXNIP-regulated control of ER stress should also be investigated further. Antioxid. Redox Signal. 38, 442-460.

Abstract 1892: Expression of bacterial heme-sequestering proteins (HeSPs) in Pichia pastoris for effective treatment of lung cancer

Abstract Heme is a central biosynthetic molecule with important implications in diverse molecular and cellular processes, including oxygen utilization and metabolism. Heme carries out a vital role in mitochondrial energy generation through oxidative phosphorylation (OXPHOS) by acting as a cofactor or prosthetic group for complexes II, II, and IV in the electron transport chain. Lung cancer is the leading cause of cancer related death in the US. Our lab has previously shown that non-small cell lung cancer (NSCLC) cells exhibit an elevated heme flux characterized by elevated heme synthesis and import. This increased heme flux correlates with an enhanced oxygen consumption and ATP production. To target this elevated heme flux, we have engineered recombinant bacterial HasA hemophores as heme-sequestering proteins (HeSPs). HeSPs bind to and sequester heme with an extremely high (pM) affinity, thereby disrupting this elevated heme flux. HeSPs display potent anti-tumor activity in mouse models of NSCLC and triple-negative breast cancer (TNBC). Here, we utilized the Pichia pastoris expression platform to achieve high-yield expression. P. pastoris is a methylotrophic yeast that has minimal endogenous protein secretion and potentially high-yields for heterologous protein expression, due to a tightly regulated alcohol oxidase gene (AOX1). The P. pastoris expression platform is generally easier to handle and requires simpler fermentation conditions than mammalian cell cultures, making it an ideal candidate for expression of recombinant bacterial proteins without endotoxin contamination.We utilized a secretion signal to direct secretion of HeSP2 into the culture medium to allow for easier protein purification. Purification was performed through ion exchange chromatography. We utilized native PAGE and heme-binding spectrum to verify that these yeast-expressed HeSPs adopt a similar conformation to those expressed in bacteria and maintain their heme-binding activity. HeSPs expressed through this P. pastoris expression system demonstrated remarkable anti-cancer efficacy in proliferation assays on NSCLC cells and SCLC (small cell lung cancer) cells. Experiments are underway to test their anti-tumor efficacy in mouse models. These experiments may suggest a novel approach to generate effective anti-cancer agents. Citation Format: Narges Salamat, Adnin Ashrafi, Tianyuan Wang, Zakia Akter, Hanling Gong, Li Zhang. Expression of bacterial heme-sequestering proteins (HeSPs) in Pichia pastoris for effective treatment of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1892.

Hypertrichosis associated with genetic conditions with head and neck alterations

INTRODUCTION: Hypertrichosis is a rare disorder in which there is an exaggerated growth of body hair in places that are not necessarily androgen-dependent, a particular feature of hirsutism. Its etiology is still questionable, with an increased incidence when associated with syndromes. This genetic association leads to numerous significant systemic and craniofacial changes, which should be recognized and considered by the dentist.OBJECTIVE: To assess, in databases, the presence of congenital hypertrichosis associated with genetic syndromes and conditions affecting the head and neck.METHODS: The search was conducted in PubMed-NCBI databases; genetic conditions along with their characteristics were available in Online Mendelian Inheritance in Man (OMIM) and in Protein®.RESULTS: The analysis was performed on 63 articles and all diseases were considered as rare. In the syndromes, prevalence of autosomal dominant inheritance was observed in 48.64%, followed by autosomal recessive in 45.9%, 1 X-linked recessive case, and 1 arising from defective mitochondrial energy generation. Among the 63 genetic conditions, 44 showed neurodevelopmental changes. Besides the craniofacial involvement itself, there is a high prevalence of alterations of the oral structures involving 47 of all conditions, including mainly dental abnormalities, palatal and gingival changes.CONCLUSION: The association of hypertrichosis with genetic components is strongly associated with major craniofacial changes. Therefore, the knowledge of the dental surgeon about the conditions that can affect the oral cavity is impressive because it is related to a correct treatment and better quality of life for the patient.

The Role of the Metabolism of Zinc and Manganese Ions in Human Cancerogenesis.

Metal ion homeostasis is fundamental for life. Specifically, transition metals iron, manganese and zinc play a pivotal role in mitochondrial metabolism and energy generation, anti-oxidation defense, transcriptional regulation and the immune response. The misregulation of expression or mutations in ion carriers and the corresponding changes in Mn2+ and Zn2+ levels suggest that these ions play a pivotal role in cancer progression. Moreover, coordinated changes in Mn2+ and Zn2+ ion carriers have been detected, suggesting that particular mechanisms influenced by both ions might be required for the growth of cancer cells, metastasis and immune evasion. Here, we present a review of zinc and manganese pathophysiology suggesting that these ions might cooperatively regulate cancerogenesis. Zn and Mn effects converge on mitochondria-induced apoptosis, transcriptional regulation and the cGAS-STING signaling pathway, mediating the immune response. Both Zn and Mn influence cancer progression and impact treatment efficacy in animal models and clinical trials. We predict that novel strategies targeting the regulation of both Zn and Mn in cancer will complement current therapeutic strategies.

МЕХАНИЗМЫ МИТОХОНДРИАЛЬНОЙ ДИСФУНКЦИИ НЕЙРОНОВ ПРИ ВОЗДЕЙСТВИИ МЫШЬЯКА И АЛЮМИНИЯ (ОБЗОР)

Exposure to neurotropic chemicals (aluminum, arsenic, etc.) as a result of pollution of environmental objects can cause disruption of the bioenergetics of nerve cells. Objectives. To analyze and summarize the literature data on the mechanisms of the effects of arsenic and aluminum on the structure and functions of neuronal mitochondria. Sources of data: literature sources reflecting the mechanisms of the influence of these neurotoxicants on neuronal mitochondria. Methods. The basis of this study was the review of literature on this topic. Results. The influence of arsenic compounds on nerve cells causes mitochondrial dysfunction due to the activation of oxidative stress, an increase in the intracellular level of Ca&lt;sup&gt;2+&lt;/sup&gt;, a decrease in the mitochondrial membrane potential and the level of calpain 1, but aluminum compounds increase the formation of reactive oxygen species (ROS) and disrupt the activity of cytochrome c-oxidase and the energy-producing function of mitochondria in various types of neurons. Mitochondrial dysfunction, caused when exposed to these metals is accompanied by the decrease in ROS resynthesis and the activation of oxidative stress, which in its turn decreases energy generation in mitochondria still to a greater extent according to the mechanism of a vicious circle («CIRCULUS VITIOSUS»). Conclusions. The presented information deepens our knowledge about the mechanisms of neuronal bioenergetics disorders under the influence of arsenic and aluminum compounds, which is the basis for further research in order to develop effective methods of prevention, detoxification and antioxidant therapy for acute and chronic arsenic and aluminum poisoning and to implement the results obtained in practical healthcare.

Try or Die: Dynamics of Plant Respiration and How to Survive Low Oxygen Conditions.

Fluctuations in oxygen (O2) availability occur as a result of flooding, which is periodically encountered by terrestrial plants. Plant respiration and mitochondrial energy generation rely on O2 availability. Therefore, decreased O2 concentrations severely affect mitochondrial function. Low O2 concentrations (hypoxia) induce cellular stress due to decreased ATP production, depletion of energy reserves and accumulation of metabolic intermediates. In addition, the transition from low to high O2 in combination with light changes—as experienced during re-oxygenation—leads to the excess formation of reactive oxygen species (ROS). In this review, we will update our current knowledge about the mechanisms enabling plants to adapt to low-O2 environments, and how to survive re-oxygenation. New insights into the role of mitochondrial retrograde signaling, chromatin modification, as well as moonlighting proteins and mitochondrial alternative electron transport pathways (and their contribution to low O2 tolerance and survival of re-oxygenation), are presented.