Beta-adrenergic agonism protects mitochondrial metabolism in the pancreatectomised rat heart.

The diabetic heart is characterised by functional, morphological and metabolic alterations predisposing it to contractile failure. Chronic sympathetic activation is a feature of the pathogenesis of heart failure, however the type 1 diabetic heart shows desensitisation to ß-adrenergic stimulation. Here, we sought to understand the impact of repeated isoprenaline-mediated ß-stimulation upon cardiac mitochondrial respiratory capacity and substrate metabolism in the 90% pancreatectomy (Px) rat model of type 1 diabetes. We hypothesised these hearts would be relatively protected against the metabolic impact of stress-induced cardiomyopathy. We found that individually both Px and isoprenaline suppressed cardiac mitochondrial respiration, but that this was preserved in Px rats receiving isoprenaline. Px and isoprenaline had contrasting effects on cardiac substrate metabolism, with increased reliance upon cardiac fatty acid oxidation capacity and altered ketone metabolism in the hearts of Px rats, but enhanced capacity for glucose uptake and metabolism in isoprenaline-treated rats. Moreover, Px rats were protected against isoprenaline-induced mortality, whilst isoprenaline elevated cGMP and protected myocardial energetic status in Px rat hearts. Our work suggests that adrenergic stimulation may be protective in the type 1 diabetic heart, and underlines the importance of studying pathological features in combination when modeling complex disease in rodents.

Medium-Chain Chlorinated Paraffins Trigger Thyroid Hormone Synthesis and Interfere with Mitochondrial Function in the Thyroid Gland.

Medium-chain chlorinated paraffins (MCCPs, C14-C17) are frequently detected in diverse environmental media. It has been proposed to be listed in Annex A of the Convention on Persistent Organic Pollutants in 2023. Although MCCPs are a crucial health concern, their toxicity remains unclear. This study investigated the toxic effects of MCCPs (0.1-50 mg/kg body weight/day) on the thyroid gland of female Sprague-Dawley rats and characterized the potential toxic pathways via transcriptomics and metabolomics approaches. MCCPs exposure caused histopathological changes to the endoplasmic reticula and mitochondria in thyroid follicular cells at a dose of 50 mg/kg bw/d and increased serum thyrotropin-releasing hormone, thyroid-stimulating hormones, and thyroxine when exposed to a higher dose of MCCPs. Transcriptomic analysis indicated the excessive expression of key genes related to thyroid hormone synthesis induced by MCCPs. Integrating the dual-omics analysis revealed mitochondrial dysfunction of the thyroid by mediating fatty acid oxidation, Kreb's cycle, and oxidative phosphorylation. Significant metabolic toxicity on the thyroid might be linked to the characteristics of the chlorine content of MCCPs. This study revealed the toxicity of MCCPs to the thyroid gland via triggering thyroid hormone synthesis and interfering with mitochondrial function, which can provide new insights into the modes of action and mechanism-based risk assessment of MCCPs.

Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.

In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. The mechanisms of regulation of mtDNA copy number and expression are not completely understood but crucially ensure the correct stoichiometric assembly of OXPHOS complexes from nuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA) on the mtDNA of diverse animal and plant species. This modification is regulated in C. elegans by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA 6mA through targeted modulation of these activities inappropriately alters mtDNA copy number and transcript levels, impairing OXPHOS function, elevating oxidative stress, and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotes the cross-generational propagation of a deleterious mtDNA. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels in vivo.

Glutamine supplementation as a novel metabolic therapeutic strategy for LIG3-dependent chronic intestinal pseudo-obstruction.

BACKGROUND AND AIMS: We recently identified a recessive syndrome due to LIG3 mutations in patients with chronic intestinal pseudo-obstruction, leukoencephalopathy and neurogenic bladder. LIG3 mutations affect mitochondrial DNA (mtDNA) maintenance, leading to defective energy production. We aimed at identifying altered molecular pathways and develop possible targeted treatments to revert / ameliorate the cellular energy impairment. METHODS: Whole transcriptome analysis was performed on patients' derived fibroblasts total RNA and controls. Mitochondrial function, mitophagy, L-Glutamine (L-Gln) supplementation effects were analyzed by live cell analysis, immunostaining and western blot. Patients were treated with Dipeptiven according to standard protocols. Patients' symptoms were analyzed by the Gastrointestinal Symptom Rating Scale questionnaire. RESULTS: We identified deregulated transcripts in mutant fibroblasts vs. controls, including overexpression of genes involved in extracellular matrix development and remodeling and mitochondrial functions. Gut biopsies of LIG3-mutant patients documented collagen and elastic fiber accumulation. Mutant fibroblasts exhibited impaired mitochondrial mitophagy indicative of dysfunctional turnover and altered Ca2+ homeostasis. L-Gln supplementation (6 mM), previously shown to increase mtDNA-defective cell survival, improved growth rate and ATP production in LIG3-mutant fibroblasts. These data led us to provide parenterally a dipeptide containing L-Gln to three siblings carrying biallelic LIG3 mutations. Compared to baseline, gastrointestinal and extra-gastrointestinal symptoms significantly improved after 8 months of treatment. CONCLUSIONS: LIG3 deficiency leads to mitochondrial dysfunction. High levels L-Gln supplementation was beneficial in LIG3-mutant cells and improved symptom severity without noticeable side effects. Our results provide a proof-of-concept to design ad hoc clinical trials with L-Gln in LIG3-mutant patients.

Optimizing Pollen Germination and Subcellular Dynamics in Pollen Tube of Torreya grandis.

Torreya grandis, a dioecious Taxaceae species of significant economic value in southeast China, presents challenges for natural pollination due to asynchronous maturation of its sex organs and low pollen vitality. In order to enhance fertilization success through artificial pollination of T. grandis, this study investigated the optimal conditions for in vitro pollen germination and pollen tube growth of T. grandis. The optimal in vitro growth medium was found to contain 29mM sucrose, 0.8mM H3BO3, 0.72mM CaCl2, and 0.32mM MgSO4, supplemented with 4µM NAA, 2µM GA3, and 5µM 2,4-D at pH=5.6. Under these conditions, we achieved a maximum pollen germination ratio of 69.99 ± 5.17% and a pollen tube length of 34.38 ± 6.04µm after 6 days germination at 28°C. FM4-64 dye and Mitotracker Red staining revealed highly dynamics of vesicles and mitochondria during germination, which were accumulated at the tip of pollen tube and exhibited biphasic movement patterns. The total number, motion rate, and movement velocity of vesicles as well as mitochondria showed an initially increase followed by a gradual decrease pattern. The presence of sucrose in the medium significantly increased the dynamics and metabolic activity of both vesicles and mitochondria, which may relate with higher pollen germination ratio and faster pollen tube growth compared to sucrose-depleted conditions. Thus, these findings shed light on the physiological characteristics of Torreya pollen germination and provide scientific information for improving Torreya fruit yield through artificial pollination.

Why does a cell function? New arguments in favor of quantum effects.

In this study, the complexities of intracellular processes have been analyzed, including DNA folding, alternative splicing, mitochondrial function, and enzyme transport in lysosomes. Based on a previously proposed hypothesis (Levinthal's generalized paradox), a conclusion is made that all abovementioned processes cannot be realized with sufficient accuracy and in a realistic timeframe within the framework of classical physics. It is unclear why the cell functions at all. For the cell to function, its internal environment must be highly structured. In this regard, the cell shares similarities with computational devices (computers). In this study, quantum models of interactions between biologically important molecules were constructed, taking into account the long-range effects. One significant aspect of these models is the special role of the phase of the wavefunction, which serves as a controlling parameter. Experiments have been proposed that may confirm or refute these models.

Inherited mitochondrial dysfunction triggered by OPA1 mutation impacts the sensory innervation fibre identity, functionality and regenerative potential in the cornea.

Mitochondrial dysfunctions are detrimental to organ metabolism. The cornea, transparent outmost layer of the eye, is prone to environmental aggressions, such as UV light, and therefore dependent on adequate mitochondrial function. While several reports have linked corneal defects to mitochondrial dysfunction, the impact of OPA1 mutation, known to induce such dysfunction, has never been studied in this context. We used the mouse line carrying OPA1delTTAG mutation to investigate its impact on corneal biology. To our surprise, neither the tear film composition nor the corneal epithelial transcriptomic signature were altered upon OPA1 mutation. However, when analyzing the corneal innervation, we discovered an undersensitivity of the cornea upon the mutation, but an increased innervation volume at 3 months. Furthermore, the fibre identity changed with a decrease of the SP + axons. Finally, we demonstrated that the innervation regeneration was less efficient and less functional in OPA1+/- corneas. Altogether, our study describes the resilience of the corneal epithelial biology, reflecting the mitohormesis induced by the OPA1 mutation, and the adaptation of the corneal innervation to maintain its functionality despite its morphogenesis defects. These findings will participate to a better understanding of the mitochondrial dysfunction on peripheral innervation.

Mfn2R364W, Mfn2G176S, and Mfn2H165R mutations drive Charcot-Marie-Tooth type 2A disease by inducing apoptosis and mitochondrial oxidative phosphorylation damage.

Charcot-Marie-Tooth type 2A (CMT2A) is a single-gene motor sensory neuropathy caused by Mfn2 mutation. It is generally believed that CMT2A involves mitochondrial fusion disruption. However, how Mfn2 mutation mediates the mitochondrial membrane fusion loss and its further pathogenic mechanisms remain unclear. Here, in vivo and in vitro mouse models harboring the Mfn2R364W, Mfn2G176S and Mfn2H165R mutations were constructed. Mitochondrial membrane fusion and fission proteins analysis showed that Mfn2R364W, Mfn2G176S, and Mfn2H165R/+ mutations maintain the expression of Mfn2, but promote Drp1 upregulation and Opa1 hydrolytic cleavage. In Mfn2H165R/H165R mutation, Mfn2, Drp1, and Opa1 all play a role in inducing mitochondrial fragmentation, and the mitochondrial aggregation is affected by Mfn2 loss. Further research into the pathogenesis of CMT2A showed these three mutations all induce mitochondria-mediated apoptosis, and mitochondrial oxidative phosphorylation damage. Overall, loss of overall fusion activity affects mitochondrial DNA (mtDNA) stability and causes mitochondrial loss and dysfunction, ultimately leading to CMT2A disease. Interestingly, the differences in the pathogenesis of CMT2A between Mfn2R364W, Mfn2G176S, Mfn2H165R/+ and Mfn2H165R/H165R mutations, including the distribution of Mfn2 and mitochondria, the expression of mitochondrial outer membrane-associated proteins (Bax, VDAC1 and AIF), and the enzyme activity of mitochondrial complex I, are related to the expression of Mfn2.

Current status and trend of mitochondrial research in lung cancer: A bibliometric and visualization analysis.

This study summarizes and analyzes the relationship between mitochondria and the pathogenesis of lung cancer. The related articles in the Web of Science core literature database are searched and collected, and the data are processed by R software, Citespace, VOSviewer, and Excel. A total of 4476 related papers were retrieved, 4476 articles from 20162 co-authors of 3968 institutions in 84 countries and published in 951 journals. Through various bibliometric analysis tools, the relationship between mitochondria and the pathogenesis of lung cancer was analyzed, the previous research results were summarized, and the potential research direction was found.

Novel mitochondrial-related gene signature predicts prognosis and immunological status in glioma.

Background: Mitochondria are the center of cellular metabolism. The relationship between mitochondria and diseases has also been studied for a long time. However, the prognostic role of mitochondrial-related genes (MRGs) in patients with glioma and their biological effects are still unclear. The aim of the study was to construct a mitochondria-related model to assess prognosis and potential biological effects like immune infiltration, gene pathway and mutation, and give some predictive chemotherapeutic agents. Methods: The data of 675 patients from The Cancer Genome Atlas (TCGA) database were used to identify MRG signature and construct a prognostic model. After validating its robustness in Chinese Glioma Genome Atlas (CGGA), two risk groups derived from the prognostic model were then conducted with Gene Set Enrichment Analysis (GSEA), immune status, mutation status and chemotherapeutic agents prediction. Results: The prognostic model built from six gene signatures can successfully predict the prognosis and reflect clinicopathological characteristics. Patients in high-risk group displayed significantly worse overall survival (OS), immunosuppression effects, and mutation markers with worse prognosis. Twelve chemotherapeutic agents with strongly correlated sensitivity and risk scores were selected as potential agents. Conclusions: The novel MRG signatures (TYMP, TSFM, MGME1, BOLA3, TRMT5, NDUFA9) can predict prognosis and immunological status in glioma.

Unraveling the complex interplay between Mitochondria-Associated Membranes (MAMs) and cardiovascular Inflammation: Molecular mechanisms and therapeutic implications.

Cardiovascular diseases (CVDs) represent a significant public health concern because of their associations with inflammation, oxidative stress, and abnormal remodeling of the heart and blood vessels. In this review, we discuss the intricate interplay between mitochondria-associated membranes (MAMs) and cardiovascular inflammation, highlighting their role in key cellular processes such as calcium homeostasis, lipid metabolism, oxidative stress management, and ERS. We explored how these functions impact the pathogenesis and progression of various CVDs, including myocardial ischemia-reperfusion injury, atherosclerosis, diabetic cardiomyopathy, cardiovascular aging, heart failure, and pulmonary hypertension. Additionally, we examined current therapeutic strategies targeting MAM-related pathways and proteins, emphasizing the potential of MAMs as therapeutic targets. Our review aims to provide new insights into the mechanisms of cardiovascular inflammation and propose novel therapeutic approaches to improve cardiovascular health outcomes.

"Unlocking Athletic Potential: Exploring Exercise Physiology from Mechanisms to Performance". Acute antioxidant supplementation and performance - should this be considered.

It is well known that a training intervention leads to mitochondrial adaptations with increased skeletal muscle mitochondrial biogenesis and function. Studies have recently indicated that skeletal muscle mitochondrial function is important for athletic performance. During exercise reactive oxygen species are released from skeletal muscle potentially leading to adaptations but maybe also to fatigue. Focus has been on how chronic antioxidant supplementation affects a training adaptation, where some studies are reporting an abolished adaptation. Whether acute antioxidant supplementation could have a positive effect on fatigue and performance is interesting and highly relevant in sports where athletes are competing over several consecutive days or on the same day, with preliminary competitions in the morning and finals in the afternoon, where it is important for the athletes to recover fast. This review provides an overview of the effects of acute antioxidant supplementation and whether it leads to improved performance and/or faster recovery in humans.

Benzopyrene represses mitochondrial fission factors and PINK1/Parkin-mediated mitophagy in primary astrocytes.

Mitochondria are essential for various physiological functions in astrocytes in the brain, such as maintaining ion and pH homeostasis, regulating neurotransmission, and modulating neuroinflammation. Mitophagy, a form of autophagy specific to mitochondria, is essential for ensuring mitochondrial quality and function. Benzo[a]pyrene (BaP) accumulates in the brain, and exposure to it is recognized as an environmental risk factor for neurodegenerative diseases. However, while the toxic mechanisms of BaP have been investigated in neurons, their effects on astrocytes-the most prevalent glial cells in the brain-are not clearly understood. Therefore, this study aims to investigate the toxic effects of exposure to BaP on mitochondria in primary astrocytes. Fluorescent probes and genetically encoded indicators were utilized to visualize mitochondrial morphology and physiology, and regulatory factors involved in mitochondrial morphology and mitophagy were assessed. Additionally, the mitochondrial respiration rate was measured in BaP-exposed astrocytes. BaP exposure resulted in mitochondrial enlargement owing to the suppression of mitochondrial fission factors. Furthermore, BaP-exposed astrocytes demonstrated reduced mitophagy and exhibited aberrant mitochondrial function and physiology, such as altered mitochondrial respiration rates, increased mitochondrial superoxide, disrupted mitochondrial membrane potential, and dysregulated mitochondrial Ca2+. These findings offer insights into the underlying toxic mechanisms of BaP exposure in neurodegenerative diseases by inducing aberrant mitophagy and mitochondrial dysfunction in astrocytes.

Leptin A deficiency affecting the mitochondrial dynamics of aged oocytes in medaka (Oryzias latipes).

Mitochondrial dysfunction and metabolic disorder have been associated to age-related subfertility, however, the precise molecular mechanism controlling the development of fertile oocytes in aging females remains elusive. Leptin plays an important role in the maintenance of energy homeostasis, as both excessive or insufficient levels can affect the body weight and fertility of mice. Here, we report that leptin A deficiency affects growth and shortens reproductive lifespan by reducing fertility in medaka (Oryzias latipes). Targeted disruption of lepa (lepa-/-) females reduced their egg laying and fertility compared to normal 3-month-old females (lepa+/+ sexual maturity), with symptoms worsening progressively at the age of 6 months and beyond. Transcriptomic analysis showed that differentially expressed genes involved in metabolic and mitochondrial pathways were significantly altered in lepa-/- ovaries compared with the normal ovaries at over 6 months old. The expression levels of the autophagy-promoting genes ulk1a, atg7 and atg12 were significantly differentiated between normal and lepa-/- ovaries, which were further confirmed by quantitative polymerase chain reaction analysis, indicating abnormal autophagy activation and mitochondrial dysfunction in oocyte development lacking lepa. Transmission electron microscopy observations further confirmed these mitochondrial disorders in lepa-deficient oocytes. In summary, these research findings provide novel insights into how leptin influences female fertility through mitochondrial-mediated oocyte development.

Vitamin D ameliorates particulate matter induced mitochondrial damages and calcium dyshomeostasis in BEAS-2B human bronchial epithelial cells.

BACKGROUND: Mitochondria is prone to oxidative damage by endogenous and exogenous sources of free radicals, including particulate matter (PM). Given the role of mitochondria in inflammatory disorders, such as asthma and chronic obstructive pulmonary disease, we hypothesized that supplementation of vitamin D may play a protective role in PM-induced mitochondrial oxidative damages of human bronchial epithelial BEAS-2B cells. METHODS: BEAS-2B cells were pretreated with 1,25(OH)2D3, an active form of vitamin D, for 1 h prior to 24-hour exposure to PM (SRM-1648a). Oxidative stress was measured by flow cytometry. Mitochondrial functions including mitochondrial membrane potential, ATP levels, and mitochondrial DNA copy number were analyzed. Additionally, mitochondrial ultrastructure was examined using transmission electron microscopy. Intracellular and mitochondrial calcium concentration changes were assessed using flow cytometry based on the expression of Fluo-4 AM and Rhod-2 AM, respectively. Pro-inflammatory cytokines, including IL-6 and MCP-1, were quantified using ELISA. The expression levels of antioxidants, including SOD1, SOD2, CAT, GSH, and NADPH, were determined. RESULTS: Our findings first showed that 24-hour exposure to PM led to the overproduction of reactive oxygen species (ROS) derived from mitochondria. PM-induced mitochondrial oxidation resulted in intracellular calcium accumulation, particularly within mitochondria, and alterations in mitochondrial morphology and functions. These changes included loss of mitochondrial membrane integrity, disarrayed cristae, mitochondrial membrane depolarization, reduced ATP production, and increased mitochondrial DNA copy number. Consequently, PM-induced mitochondrial damage triggered the release of certain inflammatory cytokines, such as IL-6 and MCP-1. Similar to the actions of mitochondrial ROS inhibitor MitoTEMPO, 1,25(OH)2D3 conferred protective effects on mtDNA alterations, mitochondrial damages, calcium dyshomeostasis, thereby decreasing the release of certain inflammatory cytokines. We found that greater cellular level of 1,25(OH)2D3 upregulated the expression of enzymatic (SOD1, SOD2, and CAT) and non-enzymatic (GSH and NADPH) antioxidants to modulate cellular redox homeostasis. CONCLUSION: Our study provides new evidence that 1,25(OH)2D3 acts as an antioxidant, enhancing BEAS-2B antioxidant responses to regulate mitochondrial ROS homeostasis and mitochondrial function, thereby enhancing epithelial defense against air pollution exposure.

HIV-1 and methamphetamine co-treatment in primary human astrocytes: TAARgeting ER/UPR dysfunction.

Objectives: Human immunodeficiency virus 1 (HIV-1) can invade the central nervous system (CNS) early during infection and persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells lead to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Substance use, including methamphetamine (METH), can increase one's risk and severity of HAND. Here, we investigate HIV-1/METH co-treatment in a key neurosupportive glial cell, astrocytes. Specifically, mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) signaling pathways, such as calcium and the unfolded protein response (UPR), are key mechanisms underlying HAND pathology and arise as potential targets to combat astrocyte dysfunction. Methods: Primary human astrocytes were transduced with a pseudotyped HIV-1 model and exposed to low-dose METH for seven days. We assessed changes in astrocyte HIV-1 infection, inflammation, mitochondrial antioxidant and dynamic protein expression, respiratory acitivity, mitochondrial calcium flux, and UPR/MAM mediator expression. We then tested a selective antagonist for METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potetnial upstream regulator of METH-induced calcium flux and UPR/MAM mediator expression. Results: Chronic METH exposure increased astrocyte HIV-1 infection. Moreover, HIV-1/METH co-treatment suppressed astrocyte antioxidant and metabolic capacity while increasing mitochondrial calcium load and protein expression of UPR messengers and MAM mediators. Notably, HIV-1 increases astrocyte TAAR1 expression, thus, could be a critical regulator of HIV-1/METH co-treatment in astrocytes. Indeed, selective antagonism of TAAR1 significantly inhibited cytosolic calcium flux and induction of UPR/MAM protein expression. Conclusion: Altogether, our findings demonstrate HIV-1/METH-induced ER-mitochondrial dysfunction in astrocytes, whereas TAAR1 may be an upstream regulator for HIV-1/METH-mediated astrocyte dysfunction.

Recent advances in mitochondria-targeting theranostic agents.

For its vital role in maintaining cellular activity and survival, mitochondrion is highly involved in various diseases, and several strategies to target mitochondria have been developed for specific imaging and treatment. Among these approaches, theranostic may realize both diagnosis and therapy with one integrated material, benefiting the simplification of treatment process and candidate drug evaluation. A variety of mitochondria-targeting theranostic agents have been designed based on the differential structure and composition of mitochondria, which enable more precise localization within cellular mitochondria at disease sites, facilitating the unveiling of pathological information while concurrently performing therapeutic interventions. Here, progress of mitochondria-targeting theranostic materials reported in recent years along with background information on mitochondria-targeting and therapy have been briefly summarized, determining to deliver updated status and design ideas in this field to readers.

Enhancement of Bone Repair in Diabetic Rats with Metformin-Modified Silicified Collagen Scaffolds.

Regenerating bone defects in diabetic rats presents a significant challenge due to the detrimental effects of reactive oxygen species and impaired autophagy on bone healing. To address these issues, a metformin-modified biomimetic silicified collagen scaffold is developed utilizing the principles of biomimetic silicification. In vitro and in vivo experiments demonstrated that the scaffold enhanced bone tissue regeneration within the diabetic microenvironment through the release of dual bio-factors. Further analysis reveals a potential therapeutic mechanism whereby these dual bio-factors synergistically promoted osteogenesis in areas of diabetic bone defects by improving mitochondrial autophagy and maintaining redox balance. The present study provides critical insights into the advancement of tissue engineering strategies aimed at bone regeneration in diabetic patients. The study also sheds light on the underlying biological mechanisms.