Glutathione is required for nitric oxide-induced chilling tolerance by synergistically regulating antioxidant system, polyamine synthesis, and mitochondrial function in cucumber (Cucumis sativus L.).

In this paper, we discussed the physiological mechanism of enhanced chilling tolerance with combined treatment of nitric oxide (NO) and reduced glutathione (GSH) in cucumber seedlings. With prolonged low temperature (10 °C/6 °C), oxidative stress improved, which was manifested as an increase the hydrogen peroxide (H2O2) and malondialdehyde (MDA), causing cell membrane damage, particularly after 48 h of chilling stress. Exogenous sodium nitroprusside (SNP, NO donor) enhanced the activity of nitric oxide synthase NOS-like, the contents of GSH and polyamines (PAs), and the cellular redox state, thus regulating the activities of mitochondrial oxidative phosphorylation components (CI, CII, CIV, CV). However, buthionine sulfoximine (BSO, a GSH synthase inhibitor) treatment drastically reversed or attenuated the effects of NO. Importantly, the combination of SNP and GSH treatment had the best effect in alleviating chilling-induced oxidative stress by upregulating the activities of antioxidant enzyme, including superoxidase dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and peroxidase (POD) and improved the PAs content, thereby increased activities of CI, CII, CIII, CIV, and CV. This potentially contributes to the maintenance of oxidative phosphorylation originating from mitochondria. In addition, the high activity of S-nitrosoglutathione reductase (GSNOR) in the combined treatment of SNP and GSH possibly mediates the conversion of NO and GSH to S-nitrosoglutathione. Our study revealed that the combined treatment with NO and GSH to synergistically improve the cold tolerance of cucumber seedlings under prolonged low-temperature stress.

Body-Wide Inactivation of the Myc-Like Mlx Transcription Factor Network Accelerates Aging and Increases the Lifetime Cancer Incidence.

The "Mlx" and "Myc" transcription factor networks cross-communicate and share many common gene targets. Myc's activity depends upon its heterodimerization with Max, whereas the Mlx Network requires that the Max-like factor Mlx associate with the Myc-like factors MondoA or ChREBP. The current work demonstrates that body-wide Mlx inactivation, like that of Myc, accelerates numerous aging-related phenotypes pertaining to body habitus and metabolism. The deregulation of numerous aging-related Myc target gene sets is also accelerated. Among other functions, these gene sets often regulate ribosomal and mitochondrial structure and function, genomic stability, and aging. Whereas "MycKO" mice have an extended lifespan because of a lower cancer incidence, "MlxKO" mice have normal lifespans and a higher cancer incidence. Like Myc, the expression of Mlx, MondoA, and ChREBP and their control over their target genes deteriorate with age in both mice and humans. Collectively, these findings underscore the importance of lifelong and balanced cross-talk between the two networks to maintain proper function and regulation of the many factors that can affect normal aging.

Targeting BRD4 mitigates hepatocellular lipotoxicity by suppressing the NLRP3 inflammasome activation and GSDMD-mediated hepatocyte pyroptosis.

Nod-like receptor family pyrin-containing protein 3 (NLRP3) inflammasome plays a pathologic role in metabolic dysfunction-associated steatohepatitis (MASH), but the molecular mechanism regulating the NLRP3 inflammasome activation in hepatocellular lipotoxicity remains largely unknown. Bromodomain-containing protein 4 (BRD4) has emerged as a key epigenetic reader of acetylated lysine residues in enhancer regions that control the transcription of key genes. The aim of this study is to investigate if and how BRD4 regulated the NLRP3 inflammasome activation and pyroptosis in MASH. Using the AML12 and primary mouse hepatocytes stimulated by palmitic acid (PA) as an in vitro model of hepatocellular lipotoxicity, we found that targeting BRD4 by genetic knockdown or a selective BRD4 inhibitor MS417 protected against hepatosteatosis; and this protective effect was attributed to inhibiting the activation of NLRP3 inflammasome and reducing the expression of Caspase-1, gasdermin D (GSDMD), interleukin (IL)-1ß and IL-6. Moreover, BRD4 inhibition limited the voltage-dependent anion channel-1 (VDAC1) expression and oligomerization in PA-treated AML12 hepatocytes, thereby suppressing the NLRP3 inflammasome activation. Additionally, the expression of BRD4 enhanced in MASH livers of humans. Mechanistically, BRD4 was upregulated during hepatocellular lipotoxicity that in turn modulated the active epigenetic mark H3K27ac at the promoter regions of the Vdac and Gsdmd genes, thereby enhancing the expression of VDAC and GSDMD. Altogether, our data provide novel insights into epigenetic mechanisms underlying BRD4 activating the NLRP3 inflammasome and promoting GSDMD-mediated pyroptosis in hepatocellular lipotoxicity. Thus, BRD4 might serve as a novel therapeutic target for the treatment of MASH.

Isolation of Mitochondria from Murine Skeletal Muscle.

Skeletal muscle is one of the largest tissues in human body. Besides enabling voluntary movements and maintaining body's metabolic homeostasis, skeletal muscle is also a target of many pathological conditions. Mitochondria occupy 10-15% volume of a muscle myofiber and regulate many cellular processes, which often determine the fate of the cell. Isolation of mitochondria from skeletal muscle provides opportunities for various multi-omics studies with a focus on mitochondria in biomedical research field. Here we describe a protocol to efficiently isolate mitochondria with high quality and purity from skeletal muscle of mice using Nycodenz density gradient ultracentrifugation.

Lipid-associated macrophages reshape BAT cell identity in obesity.

Obesity and type 2 diabetes cause a loss in brown adipose tissue (BAT) activity, but the molecular mechanisms that drive BAT cell remodeling remain largely unexplored. Using a multilayered approach, we comprehensively mapped a reorganization in BAT cells. We uncovered a subset of macrophages as lipid-associated macrophages (LAMs), which were massively increased in genetic and dietary model of BAT expansion. LAMs participate in this scenario by capturing extracellular vesicles carrying damaged lipids and mitochondria released from metabolically stressed brown adipocytes. CD36 scavenger receptor drove LAM phenotype, and CD36-deficient LAMs were able to increase brown fat genes in adipocytes. LAMs released transforming growth factor ß1 (TGF-ß1), which promoted the loss of brown adipocyte identity through aldehyde dehydrogenase 1 family member A1 (Aldh1a1) induction. These findings unfold cell dynamic changes in BAT during obesity and identify LAMs as key responders to tissue metabolic stress and drivers of loss of brown adipocyte identity.

CYP24A1 affected macrophage polarization through degradation of vitamin D as a candidate biomarker for ovarian cancer prognosis.

Ovarian cancer (OC) is a fatal gynecological malignancy with a poor prognosis in which mitochondria-related genes are involved deeply. In this study, we aim to screen mitochondria-related genes that play a role in OC prognosis and investigate its effects. Through single-cell sequencing technology and bioinformatics analysis, including TCGA ovarian cancer data analysis, gene expression signature analysis (GES), immune infiltration analysis, Gene Ontology (GO) enrichment analysis, Gene Set Enrichment Analysis (GSEA), and Principal Component Analysis (PCA), our findings revealed that CYP24A1 regulated macrophage polarization through vitamin D (VD) degradation and served as a target gene for the second malignant subtype of OC through bioinformatics analyses. For further validation, the expression and function of CYP24A1 in OC cells was investigated. And the expression of CYP24A1 was much higher in carcinoma than in paracancerous tissue, whereas the VD content decreased in the OC cell lines with CYP24A1 overexpression. Moreover, macrophages were polarized towards M1 after the intervention of VD-treated OC cell lines and inhibited the malignant phenotypes of OC. However, the effect could be reversed by overexpressing CYP24A1, resulting in the polarization of M2 macrophages, thereby promoting tumor progression, as verified by constructing xenograft models in vitro. In conclusion, our findings suggested that CYP24A1 induced M2 macrophage polarization through interaction with VD, thus promoting the malignant progression of OC.

Fatty acid preference for beta-oxidation in mitochondria of murine cultured astrocytes.

The brain utilizes glucose as a primary energy substrate but also fatty acids for the ß-oxidation in mitochondria. The ß-oxidation is reported to occur mainly in astrocytes, but its capacity and efficacy against different fatty acids remain unknown. Here, we show the fatty acid preference for the ß-oxidation in mitochondria of murine cultured astrocytes. Fatty acid oxidation assay using an extracellular flux analyzer showed that saturated or monosaturated fatty acids, palmitic acid and oleic acid, are preferred substrates over polyunsaturated fatty acids like arachidonic acid and docosahexaenoic acid. We also report that fatty acid binding proteins expressed in the astrocytes contribute less to fatty acid transport to mitochondria for ß-oxidation. Our results could give insight into understanding energy metabolism through fatty acid consumption in the brain.

Novel Mito-Nuclear Combinations Facilitate the Global Invasion of a Major Agricultural Crop Pest.

A fundamental understanding of the underlying mechanisms involved in biological invasions is crucial to developing effective risk assessment and control measures against invasive species. The fall armyworm (FAW), Spodoptera frugiperda, is a highly invasive pest that has rapidly spread from its native Americas into much of the Eastern Hemisphere, with a highly homogeneous nuclear genetic background. However, the exact mechanism behind its rapid introduction and propagation remains unclear. Here, a systematic investigation is conducted into the population dynamics of FAW in China from 2019 to 2021 and found that FAW individuals carrying "rice" mitochondria (FAW-mR) are more prevalent (>98%) than that with "corn" mitochondria (FAW-mC) at the initial stage of the invasion and in newly-occupied non-overwintering areas. Further fitness experiments show that the two hybrid-strains of FAW exhibit different adaptions in the new environment in China, and this may have been facilitated by amino acid changes in mitochondrial-encoded proteins. FAW-mR used increases energy metabolism, faster wing-beat frequencies, and lower wing loadings to drive greater flight performance and subsequent rapid colonization of new habitats. In contrast, FAW-mC individuals adapt with more relaxed mitochondria and shuttle energetics into maternal investment, observed as faster development rate and higher fecundity. The presence of two different mitochondria types within FAW has the potential to significantly expand the range of damage and enhance competitive advantage. Overall, the study describes a novel invasion mechanism displayed by the FAW population that facilitates its expansion and establishment in new environments.

Mitochondrial dysfunction and NLRP3 inflammasome: key players in kidney stone formation.

The mitochondrion serves as a critical intracellular organelle, engaging in essential roles in the regulation of energy production, oxidative stress management, calcium homeostasis, and apoptosis. One such disease that has been particularly associated with these functions is kidney stone disease (KSD), specifically calcium oxalate (CaOx). It is underpinned by oxidative stress and tissue inflammation. Recent studies have shed light on the vital involvement of mitochondrial dysfunction, the nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) inflammasome, endoplasmic reticulum stress and subsequent cell death in CaOx crystal retention and aggregation. These processes are pivotal in the pathogenesis of kidney stone formation. This review focuses on the pivotal roles of mitochondria in renal cell functions and provides an overview of the intricate interconnectedness between mitochondrial dysfunction and NLRP3 inflammasome activation in the context of KSD. It is essential to recognise the utmost significance of gaining a comprehensive understanding of the mechanisms that safeguard mitochondrial function and regulate the NLRP3 inflammasome. Such knowledge carries significant scientific implications and opens up promising avenues for the development of innovative strategies to prevent the formation of kidney stones.

Evaluating the phytotoxicological effects of bulk and nano forms of zinc oxide on cellular respiration-related indices and differential gene expression in Hordeum vulgare L.

The increasing use of nanoparticles is driving the growth of research on their effects on living organisms. However, studies on the effects of nanoparticles on cellular respiration are still limited. The remodeling of cellular-respiration-related indices in plants induced by zinc oxide nanoparticles (nnZnO) and its bulk form (blZnO) was investigated for the first time. For this purpose, barley (Hordeum vulgare L.) seedlings were grown hydroponically for one week with the addition of test compounds at concentrations of 0, 0.3, 2, and 10 mg mL-1. The results showed that a low concentration (0.3 mg mL-1) of blZnO did not cause significant changes in the respiration efficiency, ATP content, and total reactive oxygen species (ROS) content in leaf tissues. Moreover, a dose of 0.3 mg mL-1 nnZnO increased respiration efficiency in both leaves (17 %) and roots (38 %). Under the influence of blZnO and nnZnO at medium (2 mg mL-1) and high (10 mg mL-1) concentrations, a dose-dependent decrease in respiration efficiency from 28 % to 87 % was observed. Moreover, the negative effect was greater under the influence of nnZnO. The gene transcription of the subunits of the mitochondria electron transport chain (ETC) changed mainly only under the influence of nnZnO in high concentration. Expression of the ATPase subunit gene, atp1, increased slightly (by 36 %) in leaf tissue under the influence of medium and high concentrations of test compounds, whereas in the root tissues, the atp1 mRNA level decreased significantly (1.6-2.9 times) in all treatments. A dramatic decrease (1.5-2.4 times) in ATP content was also detected in the roots. Against the background of overexpression of the AOX1d1 gene, an isoform of alternative oxidase (AOX), the total ROS content in leaves decreased (with the exception of 10 mg mL-1 nnZnO). However, in the roots, where the pressure of the stress factor is higher, there was a significant increase in ROS levels, with a maximum six-fold increase under 10 mg mL-1 nnZnO. A significant decrease in transcript levels of the pentose phosphate pathway and glycolytic enzymes was also shown in the root tissues compared to leaves. Thus, the disruption of oxidative phosphorylation leads to a decrease in ATP synthesis and an increase in ROS production; concomitantly reducing the efficiency of cellular respiration.

GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development.

Mitochondria and endoplasmic reticulum contacts (MERCs) control multiple cellular processes, including cell survival and differentiation. Based on the observations that MERCs were specifically enriched in the CD4-CD8- double-negative (DN) stage, we studied their role in early mouse thymocyte development. We found that T cell-specific knockout of Hspa9, which encodes GRP75, a protein that mediates MERC formation by assembling the IP3R-GRP75-VDAC complex, impaired DN3 thymocyte viability and resulted in thymocyte developmental arrest at the DN3-DN4 transition. Mechanistically, GRP75 deficiency induced mitochondrial stress, releasing mitochondrial DNA (mtDNA) into the cytosol and triggering the type I interferon (IFN-I) response. The IFN-I pathway contributed to both the impairment of cell survival and DN3-DN4 transition blockage, while increased lipid peroxidation (LPO) played a major role downstream of IFN-I. Thus, our study identifies the essential role of GRP75-dependent MERCs in early thymocyte development and the governing facts of cell survival and differentiation in the DN stage.

Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.

Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.

Pore-Forming VDAC Proteins of the Outer Mitochondrial Membrane: Regulation and Pathophysiological Role.

Voltage-dependent anion channels (VDAC1-3) of the outer mitochondrial membrane are a family of pore-forming ß-barrel proteins that carry out controlled "filtration" of small molecules and ions between the cytoplasm and mitochondria. Due to the conformational transitions between the closed and open states and interaction with cytoplasmic and mitochondrial proteins, VDACs not only regulate the mitochondrial membrane permeability for major metabolites and ions, but also participate in the control of essential intracellular processes and pathological conditions. This review discusses novel data on the molecular structure, regulatory mechanisms, and pathophysiological role of VDAC proteins, as well as future directions in this area of research.

Unique Properties of Synaptosomes and Prospects for Their Use for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a severe neurodegenerative condition affecting millions worldwide. Prevalence of AD correlates with increased life expectancy and aging population in the developed countries. Considering that AD is a multifactorial disease involving various pathological processes such as synaptic dysfunction, neuroinflammation, oxidative stress, and improper protein folding, a comprehensive approach targeting multiple pathways may prove effective in slowing the disease progression. Cellular therapy and its further development in the form of cell vesicle and particularly mitochondrial transplantation represent promising approaches for treating neurodegeneration. The use of synaptosomes, due to uniqueness of their contents, could mark a new stage in the development of comprehensive therapies for neurodegenerative diseases, particularly AD. Synaptosomes contain unique memory mitochondria, which differ not only in size but also in functionality compared to the mitochondria in the neuronal soma. These synaptosomal mitochondria actively participate in cellular communication and signal transmission within synapses. Synaptosomes also contain other elements such as their own protein synthesis machinery, synaptic vesicles with neurotransmitters, synaptic adhesion molecules, and microRNAs - all crucial for synaptic transmission and, consequently, cognitive processes. Complex molecular ensemble ensures maintenance of the synaptic autonomy of mitochondria. Additionally, synaptosomes, with their affinity for neurons, can serve as an optimal platform for targeted drug delivery to nerve cells. This review discusses unique composition of synaptosomes, their capabilities and advantages, as well as limitations of their suggested use as therapeutic agents for treating neurodegenerative pathologies, particularly AD.

A Metastable Semiquinone Molecular Switch Modulated by Ascorbate/O2: a Study from a System Far-From-Equilibrium to Biological Assays in Mitochondria.

A molecular switch based on the metastable radical anion derived from a substituted heteroaryl quinone is described. Pyrrolil quinone thiocyanate (PQ 5) showed an interaction with the fluoride anion that was visible to the naked eye and quantified by UV/vis and 1H and 13C NMR. The metastable quinoid species formed by the interaction with F- ("ON" state) showed a molecular switching effect autocontrolled by the presence of ascorbate ("OFF" state) and back to the "ON" state by an autooxidation process, measured by visible and UV/vis spectroscopy. Due to its out-of-equilibrium properties and the exchange of matter and energy, a dissipative structural behaviour is proposed. Considering its similarity to the mechanism of coenzyme Q in oxidative phosphophorylation, PQ 5 was evaluated on Saccharomyces cerevisiae mitochondrial function for inhibition of complexes II, III and IV, reactive oxygen species (ROS) production, catalase activity and lipid peroxidation. The results showed that PQ 5 inhibited complex III activity as well as the activity of all electron transport chain (ETC) complexes. In addition, PQ 5 reduced ROS production and catalase activity in yeast. The results suggest that PQ 5 may have potential applications as a new microbicidal compound by inducing ETC dysfunction.

Mitochondrial targeted antioxidants as potential therapy for huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion in CAG repeat on huntington (Htt) gene, leading to a degeneration of GABAergic medium spiny neurons (MSNs) in the striatum, resulting in the generation of reactive oxygen species, and decrease antioxidant activity. These pathophysiological alterations impair mitochondrial functions, leading to an increase in involuntary hyperkinetic movement. However, researchers investigated the neuroprotective effect of antioxidants using various animal models. Still, their impact is strictly limited to curtailing oxidative stress and increasing the antioxidant enzyme in the brain, which is less effective in HD. Meanwhile, researchers discovered Mitochondria-targeted antioxidants (MTAXs) that can improve mitochondrial functions and antioxidant activity through the modulation of mitochondrial signaling pathways, including peroxisome proliferator-activated receptor (PPAR)-coactivator 1 (PGC-1α), dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), and Silent mating type information regulation 2 homolog 1 (SIRT-1), showing neuroprotective effects in HD. The present review discusses the clinical and preclinical studies that investigate the neuroprotective effect of MTAXs (SS31, XJB-5-131, MitoQ, bezafibrate, rosiglitazone, meldonium, coenzyme Q10, etc.) in HD. This brief literature review will help to understand the relevance of MTAXs in HD and enlighten the importance of MTAXs in future drug discovery and development.

Protective effect of Cyclo(His-Pro) on peritoneal fibrosis through regulation of HDAC3 expression.

Peritoneal dialysis is a common treatment for end-stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His-Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry was employed to identify PF-related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis-related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid-derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function.

The Role of Alpha-Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria-ER Membranes.

The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data show region-and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed multiples system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn contributes to regulating phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. Our results support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.

Mitochondrial Structure and Function in Human Heart Failure.

Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria-endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promising clinical mitochondrial targets for heart failure.

Neuroimmune modulating and energy supporting nanozyme-mimic scaffold synergistically promotes axon regeneration after spinal cord injury.

Spinal cord injury (SCI) represents a profound central nervous system affliction, resulting in irreversibly compromised daily activities and disabilities. SCI involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages, and neuronal mitochondrial energy deficit, exacerbating secondary damage and impeding axon regeneration. This study delves into the mechanistic intricacies of SCI, offering insights from the perspectives of neuroimmune regulation and mitochondrial function, leading to a pro-fibrotic macrophage phenotype and energy-supplying deficit. To address these challenges, we developed a smart scaffold incorporating enzyme mimicry nanoparticle-ceriumoxide (COPs) into nanofibers (NS@COP), which aims to pioneer a targeted neuroimmune repair strategy, rescuing CGRP receptor on macrophage and concurrently remodeling mitochondrial function. Our findings indicate that the integrated COPs restore the responsiveness of pro-inflammatory macrophages to calcitonin gene-related peptide (CGRP) signal by up-regulating receptor activity modifying protein 1 (RAMP1), a vital component of the CGRP receptor. This promotes macrophage fate commitment to an anti-inflammatory pro-resolution M2 phenotype, then alleviating glial scar formation. In addition, NS@COP implantation also protected neuronal mitochondrial function. Collectively, our results suggest that the strategy of integrating nanozyme COP nanoparticles into a nanofiber scaffold provides a promising therapeutic candidate for spinal cord trauma via rational regulation of neuroimmune communication and mitochondrial function.