Neurodegenerative diseases pose significant health challenges in the 21st century, with increasing morbidity and mortality, particularly among the elderly population. One of the key factors contributing to the pathogenesis of these diseases is the disrupted crosstalk between mitochondria and the endoplasmic reticulum. Mitochondria-associated membranes (MAMs), which are regions where the ER interfaces with mitochondria, serve as crucial platforms facilitating communication between these organelles.

This review focuses on the structural composition and functions of MAMs and highlights their roles. Additionally, in this review, we summarize the relationship between MAM dysfunction and various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and others. The involvement of key proteins such as Sig-1R, IP3R, and VAPB in maintaining ER-mitochondrial communication and their dysfunction in neurodegenerative diseases is emphasized.

Through analyzing the effects of MAM on neurodegenerative diseases, we provide the newest insights and potential therapeutic targets for the treatment of these debilitating conditions.

The mitochondria-associated endoplasmic reticulum membrane (MAM) is a crucial structure connecting mitochondria and the endoplasmic reticulum (ER), regulating intracellular calcium homeostasis, lipid metabolism, and various signaling pathways essential for arterial health. Recent studies highlight MAM's significant role in modulating vascular endothelial cells (EC) and vascular smooth muscle cells (VSMC), establishing it as a key regulator of arterial health and a contributor to vascular disease pathogenesis. Organ transplantation is the preferred treatment for end-stage organ failure, but transplant arteriosclerosis (TA) can lead to chronic transplant dysfunction, significantly impacting patient survival. TA, like other vascular diseases, features endothelial dysfunction and abnormal proliferation and migration of VSMC. Previous research on TA has focused on immune factors; the pathological and physiological changes in grafts following immune system attacks have garnered insufficient attention. For example, the potential roles of MAM in TA have not been thoroughly investigated. Investigating the relationship between MAM and TA, as well as the mechanisms behind TA progression, is essential. This review aims to outline the fundamental structure and the primary functions of MAM, summarize its key molecular regulators of vascular health, and explore future prospects for MAM in the context of TA research, providing insights for both basic research and clinical management of TA.

Mitochondrial cholesterol biology in non-steroidogenic tissues remains understudied in cell science. Although detecting cholesterol in mitochondria is challenging due to isolation difficulties, studies using mitoplasts (mitochondria stripped of their outer membrane) and imaging approaches confirm its presence in the inner mitochondrial membrane. Through analysis of published evidence and first-principles reasoning, we advance a model of cholesterol trafficking into and out of mitochondria via phospholipids at mitochondria-associated membranes (MAMs), challenging the traditional view of protein-driven transport. In this model, cholesterol enters mitochondria alongside phosphatidylserine and exits with phosphatidylethanolamine - either unchanged or in a hydroxylated form after modification by the enzyme CYP27A1. Strong cholesterol-phospholipid binding energies, ∼17 kcal/mol (71.128 kJ/mol), support this lipid-mediated mechanism, suggesting it complements protein-based pathways. Future research should explore how these mechanisms collaborate to regulate mitochondrial cholesterol trafficking. By rethinking cholesterol dynamics, we raise the possibility that cholesterol plays a larger role in mitochondrial biology, influencing membrane-dependent functions like cristae structure, respiratory efficiency and inter-organelle communication. This Perspective also highlights the potential of mitochondria to regulate both dietary and endogenous cholesterol flux and homeostasis across the cell.

The accumulation of dysfunctional giant mitochondria is a hallmark of aged cardiomyocytes. This study investigated the core mechanism underlying this phenomenon, focusing on the disruption of mitochondrial lipid metabolism and its effects on mitochondrial dynamics and autophagy, using both naturally aging mouse models and etoposide-induced cellular senescence models. In aged cardiomyocytes, a reduction in endoplasmic reticulum-mitochondrial (ER-Mito) contacts impairs lipid transport and leads to insufficient synthesis of mitochondrial phosphatidylethanolamine (PE). A deficiency in phosphatidylserine decarboxylase (PISD) further hinders the conversion of phosphatidylserine to PE within mitochondria, exacerbating the deficit of PE production. This PE shortage disrupts autophagosomal membrane formation, leading to impaired autophagic flux and the accumulation of damaged mitochondria. Modulating LACTB expression to enhance PISD activity and PE production helps maintain mitochondrial homeostasis and the integrity of aging cardiomyocytes. These findings highlight the disruption of mitochondrial lipid metabolism as a central mechanism driving the accumulation of dysfunctional giant mitochondria in aged cardiomyocytes and suggest that inhibiting LACTB expression could serve as a potential therapeutic strategy for mitigating cardiac aging and preserving mitochondrial function.

Organelles, despite having distinct functions, interact with each other. Interactions between organelles typically occur at membrane contact sites (MCSs) to maintain cellular homeostasis, allowing the exchange of metabolites and other pieces of information required for normal cellular physiology. Imbalances in organelle interactions may lead to various pathological processes. Increasing evidence suggests that abnormalorganelle interactions contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the key role of organelle interactions in NAFLD has not been fully evaluated and researched. In this review, we summarize the role of organelle interactions in NAFLD and emphasize their correlation with cellular calcium homeostasis, lipid transport, and mitochondrial dynamics.

Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.

Triptolide (TP) is an abietane-type diterpenoid isolated from the traditional Chinese herb Tripterygium wilfordii Hook. F, which is used to relieve rheumatism, alleviate joint pain and swelling, and promote blood circulation for more than 600 years in China. The most common preparations containing TP from Tripterygium wilfordii Hook F, which are Tripterygium tablets and Tripterygium glycoside tablets, are widely used in clinical for treating rheumatoid arthritis and other autoimmune diseases at present. However, the clinical application is hindered by severe systemic toxicity induced by TP, especially hepatotoxicity. It is crucial to discover potent and specific detoxification strategy for TP.

According to our previous study, TP-induced hepatotoxicity is primarily related to macrophages. This study aimed to investigate the alleviation effects of macrophage depletion on the TP-induced liver injury in mice and to explore the related mechanisms by integration of metabolomics and proteomics.

Mice were treated with clodronate liposomes to deplete macrophage before administration of triptolide. The alleviation effects were evaluated by biochemical analysis of serum and histopathology observation of the hepatic tissues. Metabolomics and proteomics were carried out to explore the mechanism of macrophage depletion on triptolide-induced liver injury. The levels of mRNA and protein of TLR4- MyD88-NF-κB axis were further detected.

The altered levels of biochemistry indicators, including aminotransferase (ALT) and aspartate aminotransferase (AST), albumin (ALB), and γ-glutamyltranspeptidase (GGT) were significantly recovered, and histopathological liver injury also showed restoring tendency in mice with macrophage depletion compared to mice with TP-treatment. The inflammation indicator interleukin-6 (IL-6) and interleukin-1β (IL-1β) were recovered significantly after depletion of macrophage. Results of metabolomics and proteomics demonstrated that macrophage depletion exerted protective effects on triptolide-induced liver injury by regulating 85 metabolites and 202 proteins. Joint analysis of multi-omics data suggested macrophage depletion could regulate lipid metabolism and maintain inflammatory homeostasis. The increased expression of NF-κB, TLR4, and MyD88 were decreased after depletion of macrophage.

TP-induced hepatotoxicity is mainly associated with dysfunction of macrophages and imbalance of inflammatory homeostasis. The findings of this study may help facilitate the development of novel therapeutic strategies.

Although mutations in human patatin-like phospholipase PNPLA6 are associated with hereditary retinal degenerative diseases, its mechanistic action in the retina is poorly understood. Here, we uncover the molecular mechanism by which PNPLA6 dysfunction disturbs retinal homeostasis and visual function. PNPLA6, by acting as a phospholipase B, regulates choline mobilization from phosphatidylcholine and subsequent choline turnover for phosphatidylcholine regeneration in retinal pigment epithelial cells. PNPLA6-driven choline is supplied from retinal pigment epithelial cells to adjacent photoreceptor cells to support their survival. Inhibition of this pathway results in abnormal morphology, proliferation, metabolism, and functions of retinal pigment epithelial and photoreceptor cells, and mice with retina-specific PNPLA6 deletion exhibit retinitis pigmentosa-like retinal degeneration. Notably, these abnormalities are entirely rescued by choline supplementation. Thus, PNPLA6 plays an essential role in retinal homeostasis by controlling choline availability for phospholipid recycling and provide a framework for the development of an ophthalmic drug target for retinal degeneration.

Treatment of cancer patients with tyrosine kinase inhibitors (TKIs) often results in hypertension, but the underlying mechanism remains unclear. This study aimed to examine the role of mitochondrial morphology and function, particularly mitochondria-associated endoplasmic reticulum membranes (MAMs), in sunitinib-induced hypertension.

Both in vitro and in vivo experiments performed to assesse reactive oxygen species (ROS), nitric oxide (NO), endothelium-dependent vasorelaxation, systemic blood pressure, and mitochondrial function in human umbilical vein endothelial cells (HUVECs) and C57BL/6 mouse aortic endothelial cells, under vehicle or sunitinib treatment condition.

Sunitinib increased mitochondrial ROS accumulation, decreased oxygen consumption rate, ATP production, and mitochondrial calcium ([Ca2+]M) levels, and impaired endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) signaling in HUVECs. In addition, sunitinib also decreased mitochondrial membrane potential, elongated mitochondria, and reduced MAMs. Remarkably, these effects were reversed by an adeno-virus linker (Ad-linker) that reinforces MAMs. Engineered augmentation of MAMs using AAV-FLT1-linker significantly mitigated sunitinib-induced hypertension, by restoring endothelium-dependent relaxation in mice, highlighting the crucial role of MAMs in this process. Further analyses revealed that sunitinib enhanced Akt-mediated expression of mitofusin 2 (MFN2), causing mitochondrial elongation, and induced dephosphorylation of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) at residues Y1737/Y1738, reducing [Ca2+]M. Our study suggests that increased MFN2 expression and IP3R1 dephosphorylation are critical in sunitinib-induced MAMs reduction and [Ca2+]M homeostasis.

Sunitinib induces mitochondrial dysfunction, Akt/MFN2-mediated decrease in MAMs and mitochondrial elongation, and IP3R1 dephosphorylation in endothelial cells, leading to endothelial dysfunction and hypertension. Our results provide the potential therapeutic targets for combating TKI-induced hypertension.

Atherosclerotic cardiovascular and cerebrovascular diseases are the number one killer of human health. In view of the important role of mitochondria in the formation and evolution of atherosclerosis, our manuscript aims to comprehensively elaborate the relationship between mitochondria and the formation and evolution of atherosclerosis from the aspects of mitochondrial dynamics, mitochondria-organelle interaction (communication), mitochondria and cell death, mitochondria and vascular smooth muscle cell phenotypic switch, etc., which is combined with genome, transcriptome and proteome, in order to provide new ideas for the pathogenesis of atherosclerosis and the diagnosis and treatment of related diseases.

Membrane contact sites (MCSs) are fundamental for intracellular communication, but their role in intercellular communication remains unexplored. We show that in plants, plasmodesmata communication bridges function as atypical endoplasmic reticulum (ER)-plasma membrane (PM) tubular MCSs, operating at cell-cell interfaces. Similar to other MCSs, ER-PM apposition is controlled by a protein-lipid tethering complex, but uniquely, this serves intercellular communication. Combining high-resolution microscopy, molecular dynamics, and pharmacological and genetic approaches, we show that cell-cell trafficking is modulated through the combined action of multiple C2 domains transmembrane domain proteins (MCTPs) 3, 4, and 6 ER-PM tethers and phosphatidylinositol-4-phosphate (PI4P) lipid. Graded PI4P amounts regulate MCTP docking to the PM, their plasmodesmata localization, and cell-cell permeability. SAC7, an ER-localized PI4P-phosphatase, regulates MCTP4 accumulation at plasmodesmata and modulates cell-cell trafficking capacity in a cell-type-specific manner. Our findings expand MCS functions in information transmission from intracellular to intercellular cellular activities.

The role of peridroplet mitochondria (PDM) in diseased liver, such as during the progression of metabolic dysfunction-associated steatohepatitis (MASH), remains unknown. We isolated hepatic cytoplasmic mitochondria (CM) and PDM from a mouse model of diet-induced MASLD/MASH to characterize their functions from simple steatosis to advanced MASH, using chow-fed mice as controls. Our findings show an inverse relationship between hepatic CM and PDM levels from healthy to steatosis to advanced MASH. Proteomics analysis revealed these two mitochondrial populations are compositionally and functionally distinct. We found that hepatic PDM are more bioenergetically active than CM, with higher pyruvate oxidation capacity in both healthy and diseased liver. Higher respiration capacity of PDM was associated with elevated OXPHOS protein complexes and increased TCA cycle flux. In contrast, CM showed higher fatty acid oxidation capacity with MASH progression. Transmission electron microscopy revealed larger and elongated mitochondria during healthy and early steatosis, which appeared small and fragmented during MASH progression. These changes coincided with higher MFN2 protein levels in hepatic PDM and higher DRP1 protein levels in hepatic CM. These findings highlight the distinct roles of hepatic CM and PDM in MASLD progression towards MASH.

Membrane contact sites (MCS) are specialized regions where organelles are closely interconnected through membrane structures, facilitating the transfer and exchange of ions, lipids, and other molecules. This proximity enables a synergistic regulation of cellular homeostasis and functions. The formation and maintenance of these contact sites are governed by specific proteins that bring organelle membranes into close apposition, thereby enabling functional crosstalk between cellular compartments. In eukaryotic cells, lipids are primarily synthesized and metabolized within distinct organelles and must be transported through MCS to ensure proper cellular function. Consequently, MCS act as pivotal platforms for lipid synthesis and trafficking, particularly in cancer cells and immune cells within the tumor microenvironment, where dynamic alterations are critical for maintaining lipid homeostasis. This article provides a comprehensive analysis of how these cells exploit membrane contact sites to modulate lipid synthesis, metabolism, and transport, with a specific focus on how MCS-mediated lipid dynamics influence tumor progression. We also examine the differences in MCS and associated molecules across various cancer types, exploring novel therapeutic strategies targeting MCS-related lipid metabolism for the development of anticancer drugs, while also addressing the challenges involved.

Mitochondrial dysfunction has been implicated in aging and various cancer development. As highly dynamic organelles, mitochondria constantly undergo fission, mediated by dynamin-related protein 1 (DRP1, gene name Dnm1l ), and fusion, regulated by mitofusin 1 (MFN1), MFN2, and optic atrophy 1 (OPA1). However, whether and how dysregulation of mitochondria dynamics would be involved in liver pathogenesis and tumorigenesis is unknown.

Dnm1l Flox/Flox ( Dnm1l F/F ), Mfn1 F/F and Mfn2 F/F mice were crossed with albumin-Cre mice to generate liver-specific Dnm1l knockout (L- Dnm1l KO), L- Mfn1 KO, L- Mfn2 KO, L- Mfn1, Mfn2 double KO (DKO), and L- Mfn1, Mfn2, Dnm1l triple KO (TKO) mice. These mice were housed for various periods up to 18 months. Some mice also received hydrodynamic tail vein injections of a Sleeping Beauty transposon-transposase plasmid system with c-MYC and YAP . Blood and liver tissues were harvested for biochemical and histological analysis.

L- Dnm1l KO mice had elevated serum alanine aminotransferase levels and increased hepatic fibrosis as early as two months of age. By 12 to 18 months, male L- Dnm1l KO mice developed spontaneous liver tumors, primarily hepatocellular adenomas. While female L- Dnm1l KO mice also developed liver tumors, their incidence was much lower. In contrast, neither L- Mfn1 KO nor L- Mfn2 KO mice had notable liver injury or tumorigenesis. However, a small portion of DKO mice developed tumors at 15-18 month-old. Increased DNA damage, senescence and compensatory proliferation were observed in L- Dnm1l KO mice but were less evident in L- Mfn1 KO, L- Mfn2 KO or DKO mice, indicating that mitochondrial fission is more important to maintain hepatocyte homeostasis and prevent liver tumorigenesis. Interestingly, further deletion of Mfn1 and Mfn2 in L- Dnm1l KO mice markedly abolished liver injury, fibrosis, and both spontaneous and oncogene-induced tumorigenesis. RNA sequencing and metabolomics analysis revealed significant activation of the cGAS-STING-interferon pathway and alterations in the tumor microenvironment pathways, alongside increased pyrimidine synthesis and metabolism in the livers of L- Dnm1l KO mice. Notably, the changes in gene expression and pyrimidine metabolism were considerably corrected in the TKO mice.

Mitochondrial dynamics and stability are essential for maintaining hepatic mitochondrial homeostasis and hepatocyte functions. Loss of hepatic DRP1 promotes liver tumorigenesis by increasing pyrimidine metabolism and activating the cGAS-STING-mediated innate immune response.

Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels.

Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated.

Fibrosis accounts for approximately one-third of disease-related deaths globally. Current therapies fail to cure fibrosis, emphasizing the need to identify new antifibrotic approaches. Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) and resultant stiffening of tissue stroma. This stiffening appropriates actomyosin-mediated mechanical tension within cells to ultimately affect cell fate decisions and function. Recent studies demonstrate that subcellular organelles are physically connected to the actin cytoskeleton and sensitive to mechanoperturbations. These insights highlight mechanisms that may contribute to the chronic organelle stress in many fibrotic diseases, including those of the lung and liver. In this review, we discuss the hypothesis that a stiffened fibrotic ECM corrupts intracellular mechanical tension to compromise organelle homeostasis. We summarize potential therapeutics that could intervene in this mechanical dialog and that may have clinical benefit for resolving pathological organelle stress in fibrosis.

Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH.

We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples.

Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840-0.979) for screening MASH.

Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses.

The project leading to these results has received funding from 'la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.

Mitochondrial dynamics plays a crucial role in the occurrence and development of non-alcoholic fatty liver diseases (NAFLD). SENP1, a SUMO-specific protease, catalyzes protein de-SUMOylation and involves in various physiological and pathological processes. However, the exact role of SENP1 in NAFLD remains unclear. Therefore, we investigated the regulatory role of SENP1 in mitochondrial dynamics during the progression of NAFLD. In the study, the NAFLD in vivo model induced by high fat diet (HFD) and in vitro model induced by free fatty acids (FFA) were established to investigate the role and underlying mechanism of SENP1 through detecting mitochondrial morphology and dynamics. Our results showed that the down-regulation of SENP1 expression and the mitochondrial dynamics dysregulation occurred in the NAFLD, evidenced as mitochondrial fragmentation, up-regulation of p-Drp1 ser616 and down-regulation of MFN2, OPA1. However, over-expression of SENP1 significantly alleviated the NAFLD, rectified the mitochondrial dynamics disorder, reduced Cyt-c release and ROS levels induced by FFA or HFD; moreover, the over-expression of SENP1 also reduced the SUMOylation levels of Drp1 and prevented the Drp1 translocation to mitochondria. Our findings suggest that the possible mechanisms of SENP1 were through rectifying the mitochondrial dynamics disorder, reducing Cyt-c release and ROS-mediated oxidative stress. The findings would provide a novel target for the prevention and treatment of NALFD.

Inorganic nitrate (NO3-) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the metabolic syndrome (MetS), type II diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Administration of NO3- to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS; however, the impact of NO3- supplementation in diet-induced obesity is not well understood. Here we investigated the whole body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat, high-sucrose (HFHS) diet for up to 12 mo of age, supplemented with 1 mM NaNO3 (or NaCl) in their drinking water. HFHS feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO3-. Furthermore, HFHS-fed mice supplemented with NO3- showed elevated levels of cardiac fibrosis and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO3- did not enhance mitochondrial β-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO3- is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction.NEW & NOTEWORTHY Inorganic nitrate has been suggested to be of therapeutic benefit in obesity-related conditions, as it increases nitric oxide bioavailability, enhances mitochondrial β-oxidation, and reverses metabolic syndrome in eNOS-/- mice. However, we here show that over 12 months nitrate was ineffective in preventing metabolic consequences in high fat, high sucrose-fed mice and worsened aspects of metabolic health, impairing cholesterol handling, increasing cardiac fibrosis, and exacerbating steatotic liver disease progression, with acceleration to hepatocellular carcinoma.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by defective lipid metabolism, which causes disease progression. MASH is also linked to various cardiometabolic risk factors, including obesity and type 2 diabetes. The contribution of defective lipid metabolism in MASH to cardiometabolic comorbidities is incompletely understood. Using hepatic lipidome profiling in eight mouse strains that differ in MASH susceptibility and patients with MASH, we show that phosphatidylserine (PS) accumulation and preservation of PS synthase 1 (PSS1) expression is associated with resistance to MASH and hypertriglyceridemia. Mechanistically, hepatocyte-specific PSS1 overexpression remodels the hepatic and very-low-density lipoprotein (VLDL) lipidome in mice with MASH. Specifically, we show an increase in VLDL ceramide that suppresses the expression and activity of lipoprotein lipase in skeletal muscle, thereby reducing VLDL-triglyceride clearance, fatty acid uptake, and lipid accumulation in muscle, overall exacerbating hypertriglyceridemia. Together, the results of this study identify hepatic PSS1 as a regulator of systemic lipoprotein metabolism.

Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) includes liver disease processes from simple fatty liver to nonalcoholic steatohepatitis, which may progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). As the incidence of HCC derived from viral hepatitis decreases, MASLD has emerged as a significant health threat, driven by lifestyle changes and rising obesity rates among patients. The pathogenesis of MASLD is complex, involving factors such as insulin resistance, gut microbiota imbalance, and genetic and epigenetic factors. In recent years, the role of mitochondrial dysfunction in MASLD has gained significant attention, involving β-oxidation imbalance, oxidative stress increase, mitophagy defects, and mitochondrial DNA (mtDNA) mutations. This article reviews the pathophysiological mechanisms of mitochondrial dysfunction in MASLD, diagnostic methods, and potential therapeutic strategies. By synthesizing current research findings, the review aims to highlight the critical role of mitochondrial dysfunction as a target for future diagnostic and therapeutic interventions. This focus could pave the way for innovative clinical strategies, ultimately improving treatment options and patient prognosis in MASLD.

Phospholipids are critical building blocks of mitochondria, and proper mitochondrial function and architecture rely on phospholipids that are primarily transported from the endoplasmic reticulum (ER). Here, we show that mitochondrial form and function rely on synthesis of phosphatidylserine (PS) in the ER through phosphatidylserine synthase (PSS), trafficking of PS from ER to mitochondria (and within mitochondria), and the conversion of PS to phosphatidylethanolamine (PE) by phosphatidylserine decarboxylase (PISD) in the inner mitochondrial membrane (IMM). Using a forward genetic screen in Drosophila, we found that Slowmo (SLMO) specifically transfers PS from the outer mitochondrial membrane (OMM) to the IMM within the inner boundary membrane (IBM) domain. Thus, SLMO is required for shaping mitochondrial morphology, but its putative conserved binding partner, dTRIAP, is not. Importantly, SLMO's role in maintaining mitochondrial morphology is conserved in humans via the SLMO2 protein and is independent of mitochondrial dynamics. Our results highlight the importance of a conserved PSS-SLMO-PISD pathway in maintaining the structure and function of mitochondria.

Excessive fat accumulation, biological clock dysregulation, viral infections, and sustained inflammatory responses can lead to liver inflammation, fibrosis, and cancer, thus promoting the development of chronic liver disease. A comprehensive understanding of the etiological factors leading to chronic liver disease and the intrinsic mechanisms influencing its onset and progression can aid in identifying potential targets for targeted therapy. Mitochondria, as key organelles that maintain the metabolic homeostasis of the liver, provide an important foundation for exploring therapeutic targets for chronic liver disease. Recent studies have shown that active ingredients in herbal medicines and their natural products can modulate chronic liver disease by influencing the structure and function of mitochondria. Therefore, studying how Chinese herbs target mitochondrial structure and function to treat chronic liver diseases is of great significance.

Investigating the prospects of herbal medicine the Lens of chronic liver disease based on mitochondrial structure and function.

A computerized search of PubMed was conducted using the keywords "mitochondrial structure", "mitochondrial function", "mitochondria and chronic liver disease", "botanicals, mitochondria and chronic liver disease".Data from the Web of Science and Science Direct databases were also included. The research findings regarding herbal medicines targeting mitochondrial structure and function for the treatment of chronic liver disease are summarized.

A computerized search of PubMed using the keywords "mitochondrial structure", "mitochondrial function", "mitochondria and chronic liver disease", "phytopharmaceuticals, mitochondria, and chronic liver disease", as well as the Web of Science and Science Direct databases was conducted to summarize information on studies of mitochondrial structure- and function-based Chinese herbal medicines for the treatment of chronic liver disease and to suggest that the effects of herbal medicines on mitochondrial division and fusion.The study suggested that there is much room for research on the influence of Chinese herbs on mitochondrial division and fusion.

Targeting mitochondrial structure and function is crucial for herbal medicine to combat chronic liver disease.

Type 2 diabetes mellitus (T2DM) intricately involves disrupted lipid metabolism. Exosomes emerge as carriers of biomarkers for early diagnosis and monitoring. This study aims to identify lipid metabolites in serum exosomes for T2DM diagnosis.

Serum samples were collected from newly diagnosed T2DM patients and age and body mass index-matched healthy controls. Exosomes were isolated using exosome isolation reagent, and untargeted/targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify and validate altered lipid metabolites. Receiver operating characteristic curve analysis was used to evaluate the diagnostic value of candidate lipid metabolites.

Serum exosomes were successfully isolated from both groups, with untargeted LC-MS/MS revealing distinct lipid metabolite alterations. Notably, phosphatidylethanolamine (PE) (22:2(13Z,16Z)/14:0) showed stable elevation in T2DM-serum exosomes. Targeted LC-MS/MS confirmed significant increase of PE (22:2(13Z,16Z)/14:0) in T2DM exosomes but not in serum. PE (22:2(13Z,16Z)/14:0) levels not only positively correlated with hemoglobin A1C levels and blood glucose levels, but also effectively distinguished T2DM patients from healthy individuals (area under the curve = 0.9141).

Our research sheds light on the importance of serum exosome lipid metabolites in diagnosing T2DM, providing valuable insights into the complex lipid metabolism of diabetes.

The intricate interaction network necessary for essential physiological functions underscores the interdependence among eukaryotic cells. Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs), specialized junctions between mitochondria and the ER, were recently discovered. These junctions participate in various cellular processes, including calcium level regulation, lipid metabolism, mitochondrial integrity maintenance, autophagy, and inflammatory responses via modulating the structure and molecular composition of various cellular components. Therefore, MAMs contribute to the pathophysiology of numerous ocular disorders, including Diabetic Retinopathy (DR), Age-related Macular Degeneration (AMD) and glaucoma. In addition to providing a concise overview of the architectural and functional aspects of MAMs, this review explores the key pathogenetic pathways involving MAMs in the development of several ocular disorders.

Hepatic steatosis, the buildup of neutral lipids in lipid droplets (LDs), is commonly referred to as metabolic dysfunction-associated steatotic liver disease when alcohol or viral infections are not involved. Metabolic dysfunction-associated steatotic liver disease encompasses simple steatosis and the more severe metabolic dysfunction-associated steatohepatitis, characterized by inflammation, hepatocyte injury, and fibrosis. Previously viewed as inert markers of disease, LDs are now understood to play active roles in disease etiology and have significant nonpathological and pathological functions in cell signaling and function. These dynamic properties of LDs are tightly regulated by hundreds of proteins that coat the LD surface, controlling lipid metabolism, trafficking, and signaling. The following review highlights various facets of LD biology with the primary goal of discussing key mechanisms through which LDs promote the development of advanced liver diseases, including metabolic dysfunction-associated steatohepatitis.

Hepatocellular carcinoma (HCC) is a leading liver cancer that significantly impacts global life expectancy and remains challenging to treat due to often late diagnoses. Despite advances in treatment, the prognosis is still poor, especially in advanced stages. Studies have pointed out that investigations into the molecular mechanisms underlying HCC, including mitochondrial dysfunction and epigenetic regulators, are potentially important targets for diagnosis and therapy. Mitoepigenetics, or the epigenetic modifications of mitochondrial DNA, have drawn wide attention for their role in HCC progression. Besides, molecular biomarkers such as mitochondrial DNA alterations and non-coding RNAs showed early diagnosis and prognosis potential. Additionally, natural compounds like alkaloids, resveratrol, curcumin, and flavonoids show promise in HCC show promise in modulating mitochondrial and epigenetic pathways involved in cancer-related processes. This review discusses how mitochondrial dysfunction and epigenetic modifications, especially mitoepigenetics, influence HCC and delves into the potential of natural products as new adjuvant treatments against HCC.

Mitochondrial functions can be regulated by membrane contact sites with the endoplasmic reticulum (ER). These mitochondria-ER contact sites (MERCs) are functionally heterogeneous and maintained by various tethers. Here, we found that REEP5, an ER tubule-shaping protein, interacts with Mitofusins 1/2 to mediate mitochondrial distribution throughout the cytosol by a new transport mechanism, mitochondrial "hitchhiking" with tubular ER on microtubules. REEP5 depletion led to reduced tethering and increased perinuclear localization of mitochondria. Conversely, increasing REEP5 expression facilitated mitochondrial distribution throughout the cytoplasm. Rapamycin-induced irreversible REEP5-MFN1/2 interaction led to mitochondrial hyperfusion, implying that the dynamic release of mitochondria from tethering is necessary for normal mitochondrial distribution and dynamics. Functionally, disruption of MFN2-REEP5 interaction dynamics by forced dimerization or silencing REEP5 modulated the production of mitochondrial reactive oxygen species (ROS). Overall, our results indicate that dynamic REEP5-MFN1/2 interaction mediates cytosolic distribution and connectivity of the mitochondrial network by "hitchhiking" and this process regulates mitochondrial ROS, which is vital for multiple physiological functions.

The incorporation of mitochondria into early eukaryotes established organelle-based biochemistry and enabled metazoan development. Diverse mitochondrial biochemistry is essential for life, and its homeostatic control via mitochondrial dynamics supports organelle quality and function. Mitochondrial crosstalk with numerous regulated cell death (RCD) pathways controls the decision to die. In this review, we will focus on apoptosis and ferroptosis, two distinct forms of RCD that utilize divergent signaling to kill a targeted cell. We will highlight how proteins and processes involved in mitochondrial dynamics maintain biochemically diverse subcellular compartments to support apoptosis and ferroptosis machinery, as well as unite disparate RCD pathways through dual control of organelle biochemistry and the decision to die.

Induction of resistin-like molecule β (Relm-β) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-β regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-β promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-β increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-β was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-β receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-β promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH.

Mitochondria are double membrane-bound organelles the network morphology of which in cells is shaped by opposing events of fusion and fission executed by dynamin-like GTPases. Mutations in these genes can perturb the form and functions of mitochondria in cell and animal models of mitochondrial diseases. An expanding array of chemical, mechanical, and genetic stressors can converge on mitochondrial-shaping proteins and disrupt mitochondrial morphology. In recent years, studies aimed at disentangling the multiple roles of mitochondrial-shaping proteins beyond fission or fusion have provided insights into the homeostatic relevance of mitochondrial morphology. Here, I review the pleiotropy of mitochondrial fusion and fission proteins with the aim of understanding whether mitochondrial morphology is important for cell and tissue physiology.

Alveolar macrophages (AM) are key effectors of the immune response and are essential for host responses to S. pneumoniae. Mitochondria are highly dynamic organelles whose function aids in regulating the cell cycle, innate immunity, autophagy, redox signaling, calcium homeostasis, and mitochondrial quality control in AM. In response to cellular stress, mitochondria can engage in stress-induced mitochondrial hyperfusion (SIMH). The current study aimed to investigate the role of Mfn1 on mitochondrial control of reactive oxygen species (ROS) in AMs and the role of Mfn1 deficiency on immune responses to S. pneumoniae. Compared to Mfn1FloxCre- controls, there were distinct histological differences in lung tissue collected from Mfn1Floxed; CreLysM mice, with less injury and inflammation observed in mice with Mfn1 deficient myeloid cells. There was a significant decrease in lipid peroxidation and ROS production in Mfn1 deficient AM that was associated with increased superoxide dismutase (SOD) and antioxidant activity. Our findings demonstrate that Mfn1 deficiency in myeloid cells decreased inflammation and lung tissue injury during S. pneumoniae infection.

Activation of mitochondrial function and heat production in adipose tissue by the modification of dietary fat is a promising strategy against obesity. However, as an important source of lipids for ketogenic and daily diets, the function of fats extracted from different adipose tissue sites was largely unknown. In this study, we illustrated the function of fats extracted from adipose tissues with different "beigeing" properties in the ketogenic diet and identified lipid profiles of fats that facilitate energy expenditure. We found that the anti-obesity effect of ketogenic diets was potentiated by using "beigeing" fat [porcine subcutaneous adipose tissue (SAT)] as a major energy-providing ingredient. Through lipidomic analyses, phosphatidylserine (PS) was identified as a functional lipid activating thermogenesis in adipose tissue. Moreover, in vivo studies showed that PS induces adipose tissue thermogenesis and alleviates diet-induced obesity in mice. In vitro studies showed that PS promotes UCP1 expression and lipolysis of adipocytes. Mechanistically, PS promoted mitochondrial function in adipocytes via the ADCY3-cAMP-PKA-PGC1α pathway. In addition, PS-PGC1a binding may affect the stability of the PGC1α protein, which further augments PS-induced thermogenesis. These results demonstrated the efficacy of dietary SAT fats in diminishing lipid accumulation and the underlying molecular mechanism of PS in enhancing UCP1 expression and mitochondrial function. Thus, our findings suggest that as dietary fat, "beigeing" fat provides more beneficial lipids that contribute to the improvement of mitochondrial function, including PS, which may become a novel, nonpharmacological therapy to increase energy expenditure and counteract obesity and its related diseases.