Diabetic wounds are open lesions that can develop on any part of the body of diabetic patients. Importantly, melatonin (Mel) exerts promotional effects on wound healing. Accordingly, this study explored the mechanism of Mel in diabetic wound healing by mediating mitochondrial function in endothelial cells.

Human umbilical vein vascular endothelial cells (HUVECs) were exposed to high glucose (HG) to mimic a diabetic environment in vitro, followed by Mel treatment. Cell viability, invasion and angiogenic capacity were evaluated with CCK-8, Transwell, and tube formation assays, respectively. CD31 protein expression was determined with Western blot. Wound healing ability was evaluated in vitro, and the levels of adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis-related proteins (Bcl-2/Bax/CytC) were also detected. To verify the role of the AMPK/SIRT1/HIF-1α pathway in diabetic wound healing, HG-induced HUVECs treated with Mel were subjected to treatment with sh-HIF-1α, AMPK inhibitor (compound c), or SIRT1 inhibitor (Nicotinamide).

HG impaired the proliferation, invasion, angiogenesis, and wound healing ability of HUVEC, increased ROS, Bax, and CytC levels, and decreased MMP and the levels of ATP and Bcl-2. Mel facilitated viability, angiogenesis, and wound healing ability while ameliorating mitochondrial dysfunction in HG-treated HUVECs. Mel activated the AMPK/SIRT1 pathway to upregulate HIF-1α in HG-treated HUVECs. HIF-1α knockdown, CC, or Nicotinamide negated the effect of Mel on HG-treated HUVECs.

Mel fosters angiogenesis and represses mitochondrial dysfunction in endothelial cells by activating the AMPK/SIRT1/HIF-1α pathway, thereby promoting diabetic wound healing.

Scutellarein (Sc), a natural flavonoid, holds potential for treating pulmonary arterial hypertension (PAH), yet its mechanisms remain unexplored. This study investigated Sc's therapeutic effects and underlying pathways in PAH. In vivo experiments demonstrated that Sc significantly attenuated right ventricular hypertension, pulmonary arterial remodeling, αSMA expression, and vascular inflammation in PAH models. In vitro, Sc suppressed hypoxia-induced proliferation, migration, inflammation, and pyroptosis in human pulmonary artery smooth muscle cells (HPASMCs). Mechanistically, Sc activated the SIRT1/NAD+ axis to restore mitochondrial homeostasis: it upregulated SIRT1 expression and elevated NAD+ levels by promoting SIRT1-mediated deacetylation of nicotinamide nucleotide transhydrogenase (NNT), thereby enhancing NNT activity. Elevated NAD+ further activated SIRT1, forming a self-reinforcing SIRT1/NNT/NAD+ feedback loop that mitigated hypoxia-induced mitochondrial dysfunction. This study identifies Sc as a novel regulator of the SIRT1-dependent NNT deacetylation pathway, which stabilizes NAD+ homeostasis to counteract HPASMCs dysregulation in PAH. These findings highlight Sc's potential as a therapeutic candidate for PAH, offering insights into targeting mitochondrial-metabolic pathways for vascular remodeling diseases.

The present study aimed to explore the role of mitochondria‑associated membranes (MAMs) as a key interface between mitochondria and the endoplasmic reticulum (ER) and to evaluate their importance in maintaining the physiological functions of these two organelles. MAMs not only act as a structural bridge between mitochondria and the ER but also widely participate in the regulation of mitochondrial biosynthesis and function, Ca2+ signal transduction, lipid metabolism, oxidative stress response and autophagy. In addition, the specific protein composition of MAMs is increasingly being recognized as having a profound impact on their function, and these proteins play a central role in regulating intercellular communication. Recently, the scientific community has accumulated a large amount of evidence supporting MAMs as potential targets for cardiovascular disease treatment. The present review focuses on the fine structure and multifunctional properties of MAMs and their mechanisms in the occurrence and development of cardiovascular diseases. The goal is to explore the mechanism of MAMs, therapeutic intervention points directly related to cardiovascular diseases, and feasibility of incorporating MAMs into the diagnostic strategy and treatment plan of cardiovascular diseases to provide novel insights and theoretical support for clinical practice in this field. MAMs have great potential as therapeutic targets for various cardiovascular diseases. This finding not only deepens the understanding of the interaction between organelles but also opens up a promising research path for the development of new therapeutic strategies for cardiovascular diseases.

Fibromyalgia (FM) is a chronic disorder that lacks both well-defined underlying causes and effective treatments. Mito-TEMPO (MIT) is a mitochondrial-specific antioxidant that has demonstrated benefits in many cancerous, renal, cardiovascular, and neurodegenerative disorders. However, the therapeutic effect of MIT on FM remains ambiguous. The objective of the current work is to illuminate the use of MIT for FM and its prospective mechanisms. Here, we used the FM rat model induced by three days of subcutaneous reserpine injection (1 mg/kg) and examined the role of MIT on SIRT1 activation and other implicated molecular pathways. Behavioral tests showed that MIT (0.7 mg/kg) can effectively alleviate the locomotor, nociceptive, and depressive-like behaviors in reserpinized rats, an effect that simultaneously reconciles the balance of monoamines in the rat brain. Western blot analysis showed that MIT up-regulates SIRT1 and improves the expression of mitochondrial dynamics proteins (DRP1 and OPA1) and the endoplasmic reticulum protein (CHOP). Furthermore, MIT treatment significantly enhanced the SOD and CAT activities and decreased the brain contents of NF-κB, TNF-α, and BAX, but significantly enriching the Bcl-2 content. Lastly, MIT treatment significantly reduced the genetic expression of miRNA-320 following RES treatment. All the measured parameters showed a significant correlation with SIRT1 expression. Our results suggest that MIT provides antioxidant, anti-apoptotic, and anti-inflammatory impacts on the FM rat model, with proposed mechanisms involved activating the SIRT1 pathway to regulate mitochondrial dynamics, endoplasmic reticulum stress, as well as miRNA-320. Thus, MIT has the potential to be an effectual drug candidate for FM treatment.

Dehydrodiisoeugenol (Deh) has demonstrated positive effects in the prevention and treatment of cardiovascular disease (CVD) caused by lipid overload, but its specific mechanism of action remains poorly understood. The aim of this study was to investigate the possible mechanisms by which Deh modulates the mitochondrial dysfunction induced by palmitate (PA) in vascular smooth muscle cells (VSMCs).

A PA-induced high-fat model of VSMCs was established, and the effect of PA on the VSMCs on function was detected by evaluating the oxidative stress and apoptosis of cells, as well as mitochondrial function. The expression of dynamin-related protein 1 (Drp1) was detected by immunofluorescence and immunoprecipitation. The key targets of Deh for the treatment of mitochondria-related diseases were screened by bioinformatics analysis and molecular docking techniques. Finally, the role of Silent information regulator 1 (SIRT1) in the treatment of PA-induced mitochondrial dysfunction in VSMCs by Deh was explored by administrating Deh as well as SIRT1 activator (CAY10602, CAY) and SIRT1 inhibitor (JGB1741, JGB).

The results showed that PA concentration-dependently increased oxidative stress and apoptosis in VSMCs, while modulating the acetylation of Drp1, promoting its expression and mitochondrial ectopia, thereby inducing mitochondrial dysfunction. Bioinformatics analysis and molecular docking indicated that SIRT1 may be a key target of Deh for the treatment of mitochondria-related diseases. Follow-up experiments revealed that Deh significantly inhibited PA-induced mitochondrial dysfunction in VSMCs by suppressing acetylation and expression of Drp1 and reducing mitochondrial ectasia, an effect that was achieved by regulating SIRT1.

Deh was able to inhibit Drp1 expression and mitochondrial ectopia by reducing Drp1 acetylation through activation of SIRT1, thereby inhibiting PA-induced mitochondrial dysfunction effects in VSMCs, ameliorating pathological processes, such as cellular oxidative stress and apoptosis, and maintaining stable cellular functions.

Mechanical ventilation (MV) is essential for patients who require life support, but undue mechanical stress leads to airway and alveolar injury, also known as ventilator-induced lung injury (VILI). MV induces changes in pulmonary endothelial barrier integrity by affecting cell junction proteins. The mechanisms of disruption of endothelial barrier integrity during VILI are still unclear. This study aimed to investigate the roles and mechanisms by which ASK1-interacting protein-1 (AIP1), G-protein pathway suppressor 2 (GPS2), and sirtuin 1 (SIRT1) affect VILI. Human lung microvascular endothelial cells (HLMVECs) were transfected with AIP1 small interfering RNA (siRNA), GPS2 siRNA, GPS2 cDNA, and SIRT1 siRNA and subjected to 20% cyclic stretch (CS). C57BL/6N mice were pretreated with the SIRT1 siRNA before MV. We found that CS of 20% activated oxidative stress, increased the reactive oxygen species (ROS) production, and disrupted the pulmonary endothelial cell barrier integrity. AIP1 depletion increased the ROS production and aggravated the disruption of endothelial barrier integrity. Loss of GPS2 decreased the level of AIP1, leading to low expression levels of cell junction proteins. These effects were alleviated by GPS2 overexpression. SIRT1 depletion induced a decrease in GPS2 and AIP1, and increased the ROS production, resulting in decreased expression levels of cell junction proteins. Furthermore, VILI was exacerbated by increased cytokine production (IL-6 and IL-1β), pulmonary oedema, and an elevated wet/dry weight ratio in SIRT1-depleted mice under MV. These results suggest that cyclic mechanical stretching activated oxidative stress and disrupted the expression of cell junction proteins. The SIRT1/GPS2/AIP1 axis influences the production of ROS to regulate the pulmonary endothelial cell barrier integrity during VILI.

Critical limb ischemia (CLI) faces high rates of amputation and mortality. Despite advancements in surgical and endovascular interventions, their invasiveness and restricted applicability leave many CLI patients classified as "no-option" cases. Therapeutic angiogenesis strategies offer prospects for revascularization, but their efficacy remains suboptimal. Herein, we developed a nanomedicine, mitochondria-targeted zinc-doped ascorbic acid-derived carbon dots (TPP-Zn@ACDs), which simultaneously restores mitochondrial function and amplifies regenerative signaling to synergistically boost angiogenesis in ischemic limbs. TPP-Zn@ACDs integrate potent antioxidative properties of carbon dots and the pro-regenerative effects of Zn2+, with triphenylphosphine (TPP) and polyethylene glycol (PEG) functionalization endowing precise mitochondrial targeting and enhanced biocompatibility, thereby localizing therapeutic effects to the core of oxidative stress mitigation and regenerative signaling transduction. In vitro, TPP-Zn@ACDs improved mitochondrial function by reducing reactive oxygen species, restoring mitochondrial membrane potential and enhancing ATP production, through activation of the SIRT1/PGC-1α signaling pathway. Further, the proliferation, migration, and tube formation activities of endothelial cells were increased, while hypoxia-induced apoptosis and necrosis was inhibited effectively. Notably, leveraging mitochondrial restoration in endothelial cells, TPP-Zn@ACDs subsequently reprogrammed macrophages from an M1 pro-inflammatory phenotype to an M2 anti-inflammatory phenotype. In vivo, TPP-Zn@ACDs demonstrated remarkable therapeutic efficacy in a mouse CLI model, achieving robust blood flow recovery, increased microvascular density, and improved immune microenvironment. Together, this study proposes TPP-Zn@ACDs as a versatile engineering nanomedicine for mitochondria-targeted therapy, providing a scalable approach to breakthrough angiogenic efficacy in ischemic diseases.

Replacing autologous nerve grafts with nerve conduits is the prevailing direction for the treatment of peripheral nerves, though the repair of hollow nerve conduits remains unsatisfactory. In this study, cysteinylated zein (l-Zein) was prepared through a disulfide exchange reaction between the disulfide bonds of cysteine (Cys) and those of zein (Zein). Subsequently, electrospinning was utilized to fabricate hollow nerve conduits loaded with berberine (BBR) by means of hydrogen bonding and physical encapsulation. Hydrogels were prepared by ionic cross-linking of Zein with pectin (Pec), and were subsequently loaded with melatonin (MT) and graphene oxide (GO) through physical adsorption and encapsulation. A hydrogel was then injected into a hollow catheter to form a hydrogel composite nerve conduit (l-ZBZPGM). The hydrogels exhibited a continuous porous network structure with pore size distribution between 100 and 200 μm. Most of the hydrogels exhibited porosity exceeding 70% and the compressive modulus was 0.42 ± 0.025 MPa. A hydrogel exhibited a residual mass ratio of 35.15% ± 1.87% at the end of the 30 d degradation period, achieved peak release on day 18 with a release rate of 83.31% ± 3.64%, and had an electrical conductivity of 1.23 ± 0.482 × 10-3 S cm-1, meeting the requirements for nerve repair. The lack of cytotoxicity and the anti-inflammatory and antioxidant properties of l-ZBZPGM were demonstrated using RSC96 cells and Raw264.7 cells. Additionally, through electrical stimulation experiments, it was proven that the addition of GO can promote the proliferation of nerve cells. The biological materials used in this study are of simple composition, and their degradation products may have a minimal impact on the microenvironment. The findings suggested that l-ZBZPGM was more conductive to peripheral nerve regeneration.

Diabetes mellitus, as a common chronic disease, easily leads to significant changes in the structure of the eye, among which diabetic cataract is particularly common. Although surgery is the main treatment for this complication, it may be accompanied by postoperative complications. Therefore, it is particularly important to develop specific drugs for diabetic cataract, aiming to fundamentally reduce its incidence and reduce the need for surgery. At present, the greatest challenge is to develop therapeutic agents with multiple synergistic effects based on the complex pathogenesis of cataract. 1-Acetyl-5-phenyl-1 H-pyrrol-3-ylacetate (APPA) is designed based on the pathological mechanism as a potential drug to alleviate the occurrence of diabetic cataract. Our observations suggest that APPA is more effective than bendazaclysine in alleviating high galactose-induced oxidative stress (The malondialdehyde content in the APPA group and bendazaclysine group was significantly reduced to 0.45-fold and 0.58-fold compared to the high galactose-induced group, respectively.) and apoptosis (The apoptosis rate in the APPA group and bendazaclysine group was significantly reduced to 0.28-fold and 0.35-fold compared to the high galactose-induced group, respectively.) in lens epithelial cells by increasing antioxidant enzyme activity, and restoring mitochondrial homeostasis. Mechanistic studies have shown that APPA restoration of mitochondrial homeostasis is mediated through the SIRT1-PGC-1α pathway. In the galactose-induced cataract rat model, APPA is effective in alleviating the occurrence of galactose-induced cataract. In conclusion, APPA with multiple synergistic functions may be a potential drug to alleviate the occurrence of diabetic cataract, and it has a wider range of indications than benzydalysine.

HFpEF is a prevalent and complex type of heart failure. The concurrent presence of conditions such as obesity, hypertension, hyperglycemia, and hyperlipidemia significantly increase the risk of developing HFpEF. Mitochondria, often referred to as the powerhouses of the cell, are crucial in maintaining cellular functions, including ATP production, intracellular Ca2+ regulation, reactive oxygen species generation and clearance, and the regulation of apoptosis. Exercise plays a vital role in preserving mitochondrial homeostasis, thereby protecting the cardiovascular system from acute stress, and is a fundamental component in maintaining cardiovascular health. In this study, we review the mitochondrial dysfunction underlying the development and progression of HFpEF. Given the pivotal role of exercise in modulating cardiovascular diseases, we particularly focus on exercise as a potential therapeutic strategy for improving mitochondrial function. Graphical abstract Note: This picture was created with BioRender.com.

Human dental pulp stem cells (hDPSCs) exhibit amazing therapeutic abilities in a variety of diseases due to their remarkable self-renewal capacity and multi-differentiation potential. However, their therapeutic potential could be weakened by various factors such as oxidative stress in cell survival microenvironment In Vivo. Here, we explored the protective effect and mechanism of melatonin (Mel) on hDPSCs transplanted in a type 1 diabetes mellitus (T1DM) rat model. Nicotinamide adenine dinucleotide (NAD+) metabolism and mitochondrial function were remarkably impaired in T1DM rats caused by oxidative stress, while the combination of Mel and post-hDPSCs transplantation could rebalance NAD+ homeostasis through regulating NAMPT-NAD+-SIRT1 axis. Furthermore, Mel significantly reduced intracellular and mitochondrial reactive oxygen species, and alleviated cell senescence and apoptosis of hDPSCs exposed to hydrogen peroxide through ameliorating NAD+ depletion and mitochondrial dysfunction. The protective role of Mel could be extremely essential to stem cells in tissue engineering and regenerative medicine.

Macrophages are vital sentinels in innate immunity, and their functions cannot be performed without internal metabolic reprogramming. Mitochondrial dynamics, especially mitochondrial fusion and fission, contributes to the maintenance of mitochondrial homeostasis. The link between mitochondrial dynamics and macrophages in the past has focused on the immune function of macrophages. We innovatively summarize and propose a link between mitochondrial dynamics and macrophage metabolism. Among them, fusion-related FAM73b, MTCH2, SLP-2 (Stomatin-like protein 2), and mtSIRT, and fission-related Fis1 and MTP18 may be the link between mitochondrial dynamics and macrophage metabolism association. Furthermore, post-translational modifications (PTMs) of mtSIRT play prominent roles in mitochondrial dynamics-macrophage metabolism connection, such as deacetylates and hypersuccinylation. MicroRNAs such as miR-150, miR-15b, and miR-125b are also possible entry points. The metabolic reprogramming of macrophages through the regulation of mitochondrial dynamics helps improve their adaptability and resistance to adverse environments and provides therapeutic possibilities for various diseases.

Aging is a biological process along with systemic and multiple organ dysfunction. It is more and more recognized that aging is a systemic disease instead of a single-organ functional disorder. Systemic aging plays a profound role in multiple diseases including neurodegenerative diseases, cardiovascular diseases, and malignant diseases. Aged organs communicate with other organs and accelerate aging. Skeletal muscle, heart, bone marrow, skin, and liver communicate with each other through organ-organ crosstalk. The crosstalk can be mediated by metabolites including lipids, glucose, short-chain fatty acids (SCFA), inflammatory cytokines, and exosomes. Metabolic disorders including hyperglycemia, hyperinsulinemia, and hypercholesterolemia caused by chronic diseases accelerate hallmarks of aging. Systemic aging leads to the destruction of systemic hemostasis, causes the release of inflammatory cytokines, senescence-associated secretory phenotype (SASP), and the imbalance of microbiota composition. Released inflammatory factors further aggregate senescence, which promotes the aging of multiple solid organs. Targeting senescence or delaying aging is emerging as a critical health strategy for solving age-related diseases, especially in the old population. In the current review, we will delineate the mechanisms of organ crosstalk in systemic aging and age-related diseases to provide therapeutic targets for delaying aging.

Melatonin exhibits various biological functions, including regulation of circadian and endocrine rhythms, anti-inflammatory, and antioxidant effects. Aging and damaged mitochondria are major sources of oxidative stress (OS), and mitochondrial quality control (MQC) is crucial for maintaining normal mitochondrial function. Myocardial ischemia-reperfusion injury is a major complication that can arise during reperfusion therapy for coronary heart disease. However, effective intervention strategies are currently lacking. Mitochondrial dysfunction and OS are considered central mechanisms of myocardial reperfusion injury, with mitochondrial-targeted interventions being a potential treatment direction. Recent studies have shown that melatonin improves mitochondrial structure and function through multiple pathways. This review discusses the mechanisms by which melatonin ameliorates myocardial ischemia-reperfusion injury, focusing on MQC, and explores its potential applications in the prevention and treatment of myocardial ischemia-reperfusion injury.

Calycosin‑7‑O‑β‑D‑glucoside (CG), a major active ingredient of Astragali Radix, exerts neuroprotective effects against cerebral ischemia; however, whether the effects of CG are associated with mitochondrial protection remains unclear. The present study explored the role of CG in improving mitochondrial function in a HT22 cell model of oxygen‑glucose deprivation/reperfusion (OGD/R). The Cell Counting Kit‑8 assay, flow cytometry, immunofluorescence and western blotting were performed to investigate the effects of CG on mitochondrial function. The results demonstrated that mitochondrial function was restored after treatment with CG, as indicated by reduced mitochondrial reactive oxygen species levels, increased mitochondrial membrane potential and improved mitochondrial morphology. Overactivated mitophagy was revealed to be inhibited by the regulation of proteins involved in fission [phosphorylated‑dynamin‑related protein 1 (Drp1) and Drp1] and mitophagy (LC3, p62 and translocase of outer mitochondrial membrane 20), and mitochondrial biogenesis was demonstrated to be enhanced by increased levels of sirtuin 1 (SIRT1) and peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α). In addition, neuronal apoptosis was ameliorated by CG, as determined by a decreased rate of apoptosis, and levels of caspase‑3 and Bcl‑2/Bax. In conclusion, the present study demonstrated that CG may alleviate OGD/R‑induced injury by upregulating SIRT1 and PGC‑1α protein expression, and reducing excessive mitochondrial fission and overactivation of mitophagy.

Programmed cell death, including necroptosis, plays a critical role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Silent information regulator 1 (SIRT1) has been identified as a potential therapeutic target for CIRI, yet its precise role in regulating necroptosis remains controversial. Furthermore, the potential interaction between SIRT1 and receptor-interacting protein kinase 1 (RIP1) in this context is not fully understood. Sanpian Decoction (SPD), a classical traditional herbal formula, was previously shown to enhance SIRT1 expression in our studies. Our findings demonstrated that, both in vivo and in vitro, CIRI was associated with a decrease in SIRT1 levels and phosphorylated dynamin-related protein 1 (p-DRP1) at Ser637, alongside an increase in RIP1 and other necroptosis-related proteins. Co-immunoprecipitation and immunofluorescence analyses revealed a weakened interaction between SIRT1 and RIP1. Furthermore, abnormal mitochondrial fission and dysfunction were mediated through the phosphoglycerate mutase 5-DRP1 pathway. Notably, SPD treatment improved neurological outcomes and reversed these pathological changes by enhancing the SIRT1-RIP1 interaction. In conclusion, this study suggests that SIRT1 is a promising therapeutic target for CIRI, capable of inhibiting necroptosis and mitigating mitochondrial fission via the SIRT1-RIP1 pathway. SPD exhibits therapeutic potential by activating SIRT1, thereby attenuating necroptosis and mitochondrial fission during CIRI.

Lipotoxicity is a significant factor in the pathogenesis of diabetic cardiomyopathy (DbCM), a condition characterized by mitochondrial fragmentation and pyroptosis. Mitochondrial fission protein 1 (FIS1) plays a role in mitochondrial fission by anchoring dynamin-related protein 1 (DRP1). However, the specific contribution of FIS1 to DbCM remains unclear. This study aims to clarify how lipotoxicity-induced upregulation of FIS1 affects mitochondrial fragmentation and the mechanisms linking this fragmentation to NLRP3-dependent pyroptosis in DbCM.

To model lipotoxicity in DbCM, we used db/db mice and primary neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA) and conducted a series of in vivo and in vitro experiments. Gain- and loss-of-function studies on NRCMs were performed using pharmacological inhibitors and small interfering RNA (siRNA) transfection, and we assessed the expression and function of FIS1, mitochondrial dynamics, mitochondrial reactive oxygen species (mitoROS) production, NLRP3-dependent pyroptosis, and their interrelationships.

Our results show that in the myocardium of db/db mice, NLRP3-dependent pyroptosis is associated with upregulation of FIS1, mitochondrial fragmentation, and increased oxidative stress. In NRCMs subjected to PA, the application of VX-765 and MCC950 to inhibit caspase-1 and NLRP3, respectively, significantly reduced pyroptosis. Additionally, pretreatment with Mito-TEMPO (MT) demonstrated that mitoROS are critical initiators for NLRP3 inflammasome activation and subsequent pyroptosis. Furthermore, PA-induced upregulation of FIS1 exacerbates mitochondrial fragmentation. Downregulation of FIS1 or inhibition of FIS1/DRP1 interaction reversed mitochondrial fragmentation, reduced mitoROS levels, and mitigated pyroptosis.

Lipotoxicity-induced FIS1 upregulation exacerbates mitochondrial fragmentation through its interaction with DRP1, leading to increased mitoROS production and the initiation of NLRP3-dependent pyroptosis in DbCM. Therefore, targeting FIS1 emerges as a potential therapeutic approach for managing DbCM.

Cardiovascular diseases (CVDs) are the leading causes of death and illness worldwide. While there have been advancements in the treatment of CVDs using medication and medical procedures, these conventional methods have limited effectiveness in halting the progression of heart diseases to complete heart failure. However, in recent years, the hormone melatonin has shown promise as a protective agent for the heart. Melatonin, which is secreted by the pineal gland and regulates our sleep-wake cycle, plays a role in various biological processes including oxidative stress, mitochondrial function, and cell death. The Sirtuin (Sirt) family of proteins has gained attention for their involvement in many cellular functions related to heart health. It has been well established that melatonin activates the Sirt signaling pathways, leading to several beneficial effects on the heart. These include preserving mitochondrial function, reducing oxidative stress, decreasing inflammation, preventing cell death, and regulating autophagy in cardiac cells. Therefore, melatonin could play crucial roles in ameliorating various cardiovascular pathologies, such as sepsis, drug toxicity-induced myocardial injury, myocardial ischemia-reperfusion injury, hypertension, heart failure, and diabetic cardiomyopathy. These effects may be partly attributed to the modulation of different Sirt family members by melatonin. This review summarizes the existing body of literature highlighting the cardioprotective effects of melatonin, specifically the ones including modulation of Sirt signaling pathways. Also, we discuss the potential use of melatonin-Sirt interactions as a forthcoming therapeutic target for managing and preventing CVDs.

Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all 3 unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. However, transcriptional regulation of mitochondrial homeostasis by eIF2α phosphorylation during ER stress is not fully understood. Here, we report that the eIF2α phosphorylation-activating transcription factor 4 (ATF4) axis is required for the expression of multiple transcription factors, including nuclear factor erythroid 2-related factor 2 and its target genes responsible for mitochondrial homeostasis during ER stress. eIF2α phosphorylation-deficient (A/A) cells displayed dysregulated mitochondrial dynamics and mitochondrial DNA replication, decreased expression of oxidative phosphorylation complex proteins, and impaired mitochondrial functions during ER stress. ATF4 overexpression suppressed impairment of mitochondrial homeostasis in A/A cells during ER stress by promoting the expression of downstream transcription factors and their target genes. Our findings underscore the importance of the eIF2α phosphorylation-ATF4 axis for maintaining mitochondrial homeostasis through transcriptional reprogramming during ER stress.

Ischemic heart disease (IHD) is associated with high morbidity and mortality rates. Reperfusion therapy is the best treatment option for this condition. However, reperfusion can aggravate myocardial damage through a phenomenon known as myocardial ischemia/reperfusion (I/R) injury, which has recently gained the attention of researchers. Several studies have shown that Chinese herbal medicines and their natural monomeric components exert therapeutic effects against I/R injury. This review outlines the current knowledge on the pathological mechanisms through which mitochondria participate in I/R injury, focusing on the issues related to energy metabolism, mitochondrial quality control disorders, oxidative stress, and calcium. The mechanisms by which mitochondria mediate cell death have also been discussed. To develop a resource for the prevention and management of clinical myocardial I/R damage, we compiled the most recent research on the effects of Chinese herbal remedies and their monomer components.

Dysfunction in podocyte mitophagy has been identified as a contributing factor to the onset and progression of diabetic nephropathy (DN), and BMAL1 plays an important role in the regulation of mitophagy. Thus, this study intended to examine the impact of BMAL1 on podocyte mitophagy in DN and elucidate its underlying mechanisms.

High D-glucose (HG)-treated MPC5 cells was used as a podocyte injury model for investigating the potential roles of BMAL1 in DN. Mitophagy was examined by detecting autophagosomes using transmission electron microscopy, and detecting the colocalization of LC3 and Tom20 using immunofluorescence staining. The interaction between BMAL1 and SIRT1 was conducted by immunoprecipitation (Co-IP) assay.

In HG-induced podocyte injury model, we found that BMAL1 and SIRT1 mRNA level was significantly decreased, and positively correlated with mitophagy dysfunction. BMAL1 overexpression could ameliorate HG-induced podocyte injury, evidenced by improved cell viability, decreased cell apoptosis and inflammatory cytokines expression (TNF-α, IL-1β, and IL-6). BMAL1 overexpression could promote podocyte mitophagy coupled with increased expression of mitophagy markers PINK1 and Parkin. In terms of mechanism, Co-IP suggested that BMAL1 could interact with SIRT1. SIRT1 inhibitor Ex-527 addition obviously inhibit the effect of BMAL1 overexpression on the mitophagy, demonstrating that BMAL1 may act on mitophagy by SIRT1//PGC-1α axis.

Our in vitro experiments demonstrate that BMAL1/SIRT1/PGC-1α pathway may protect podocytes against HG-induced DN through promoting mitophagy.

The field of hydrogen medicine has garnered extensive attention since Professor Ohsawa established that low concentrations of hydrogen (2%-4%) exert antioxidant effects. The present study aimed to evaluate the therapeutic effect of molecular hydrogen in a CUMS rat model.

A total of 40 SD rats were randomly divided into a control group, a model group, a hydrogen group, and a positive drug group. Four weeks post-modeling, hydrogen inhalation and other treatments were administered. Behavioral, biochemical, and immunohistochemical evaluations were performed after treatment.

Hydrogen inhalation alleviated depressive behavior and hippocampal neuronal damage in CUMS rats, as well as restored the levels of neurotransmitters, inflammatory factors, and oxidative stress. Moreover, it maintained mitochondrial homeostasis and up-regulated the expression of PGC-1α, PINK1, and Parkin.

The results collectively indicated that hydrogen significantly attenuated CUMS-induced depressive-like behavior and monoamine neurotransmitter deficiency, as well as protected the brain from oxidative stress and inflammatory damage and effectively preserved mitochondrial homeostasis.

Rhein is a natural active ingredient in traditional Chinese medicine that has attracted much attention due to its wide range of pharmacological activities. However, its clinical application is limited by low water solubility, poor oral absorption, and potential toxicity to the liver and kidneys. Recently, advanced extraction and synthesis techniques have made it possible to develop derivatives of rhein, which have better pharmacological properties and lower toxicity. This article comprehensively summarizes the biological activity and action mechanism of rhein. Notably, we found that TGF-β1 is the target of rhein improving tissue fibrosis, while NF-κB is the main target of its anti-inflammatory effect. Additionally, we reviewed the current research status of the pharmacokinetics, toxicology, structural optimization, and potential drug applications of rhein and found that the coupling and combination therapy of rhein and other active ingredients exhibit a synergistic effect, significantly enhancing therapeutic efficacy. Finally, we emphasize the necessity of further studying rhein's pharmacological mechanisms, toxicology, and development of analogs, aiming to lay the foundation for its widespread clinical application as a natural product and elucidate its prospects in modern medicine.

Cardiovascular disease (CVD) poses a major risk to human health and exert a heavy burden on individuals, society, and healthcare systems. Therefore, it is critical to identify CVD's underlying mechanism(s) and target them using effective agents. Natural compounds have shown promise as antioxidants with cardioprotective functions against CVD injuries due to their antioxidative solid capacity and high safety profile. Several CVDs, such as heart failure, ischemia/reperfusion, atherosclerosis, and cardiomyopathies, are closely linked to mitochondrial dysfunction. It is well established that activating the AMPK/SIRT1/PGC-1α pathway during CVD promotes mitochondrial function. Therefore, targeting the AMPK/SIRT1/PGC-1α pathway provides a foundation for novel therapeutic strategies to combat CVD. A key goal of our search was to find natural compounds that target this biological pathway and have beneficial effects on CVD.

The flavonoid compound chinonin is one of the main active components of Rhizoma anemarrhena with multiple activities, including anti-inflammatory and antioxidant properties, protection of mitochondrial function and regulation of immunity. In this paper, we reviewed recent research progress on the protective effect of chinonin on brain injury in neurological diseases. "Chinonin" OR "Mangiferin" AND "Nervous system diseases" OR "Neuroprotection" was used as the terms for search in PumMed. After discarding duplicated and irrelevant articles, a total of 23 articles relevant to chinonin published between 2012 and 2023 were identified in our study.

To use H9c2 cardiomyocytes to establish a diabetic cardiomyopathic model by exposing these cells to high glucose (HG), followed by treating them with melatonin (MEL) or plasmid vectors overexpressing FUN14 Domain Containing 1 (FUNDC1).

We employed quantitative real-time PCR, mitochondrial staining, and biochemical assays to measure the activity of various antioxidant and mitochondrial complex functions under various treatment conditions.

Our results showed that HG induced the expression of FUNDC1 and increased mitochondrial oxidative stress and fragmentation, while MEL treatment reversed most of these pathological effects. Moreover, HG exposure activated dynamin-related protein 1 expression and its translocation to mitochondria. Modulation of AMP-activated protein kinase level was found to be another pathological hallmark. In silico molecular docking, analysis revealed that MEL could directly bind the catalytic groove of FUNDC1 through Van der Waal's force and hydrogen bonding. Finally, MEL ameliorated diabetic cardiomyopathy-induced mitochondrial injury through FUNDC1 in vivo.

Hyperglycemia induced mitochondrial fragmentation and altered electron transport chain complex functions, which could be ameliorated by MEL treatment, suggesting its potential as a cardiovascular therapeutic.

Atrazine (ATR) is a widespread environmental herbicide that seriously affects agricultural work and human safety. Melatonin (MLT) as an endogenous neuroendocrine hormone is widely found in animals and plants, which have antioxidant and anti-inflammatory effects. Pink1/Parkin-mediated mitophagy keeps normal physiological processes by degrading damaged mitochondria in cells. Therefore, we investigated the potential role and mechanism of MLT in ATR-induced toxic injury of the spleen. The results showed that MLT alleviated ATR-induced unclear boundary between the white pulp and the red pulp of the spleen. It is also shown that ATR resulted in swollen mitochondria, partial extinction of mitochondrial membranes and cristae, and increased mitophagy under the action of MLT. ATR-induced reactive oxygen species (ROS) activates the Pink1/Parkin pathway, which guides mitophagy development and then causes the activation of TLR4/NF-κB inflammatory pathway. Meanwhile, these damages further exacerbated the production of NLRP3 inflammasomes, leading to spleen necrosis. Interestingly, these changes were improved after MLT treatment. Collectively, we found that MLT alleviates ATR-induced immune impairment in splenic macrophages via regulating Parkin-TLR4-NLRP3 axis which elucidates the effect of melatonin on the spleen and provides a novel perspective on melatonin in splenic inflammatory injury treatment.

There is no effective treatment for diabetes-related atrial remodeling currently. This study aimed to investigate the effects of renal denervation (RDN) on diabetes-related atrial remodeling and explore the related mechanisms. A type 2 diabetes mellitus model was established by high-fat diet feeding and low-dose streptozotocin injection in Sprague‒Dawley rats. After successful modeling, the diabetic rats were randomly assigned to two groups according to whether they were subjected to RDN or sham RDN surgery. At the end of the experiment, cardiac function and structure were evaluated by echocardiography and histology, respectively. Mitochondrial morphology, function and mitochondrial dynamics were assessed by multiple methods. Mdivi1 was used to verify the mechanism by which RDN improves atrial remodeling. In the 10th week, diabetic rats exhibited obvious atrial remodeling, including atrial enlargement and diastolic dysfunction. Pathological staining showed that diabetic rats had cardiomyocyte hypertrophy and interstitial fibrosis in atrial tissues. In terms of mitochondrial morphology and function, diabetic rats exhibited fragmented mitochondria, reduced adenosine triphosphate production and decreased mitochondrial membrane potential levels. Abnormal mitochondrial dynamics in diabetic rats were characterized by the inhibition of mitochondrial fusion, excessive mitochondrial fission, and the suppression of mitophagy. However, RDN effectively ameliorated diabetes-induced pathological atrial remodeling. In addition, RDN significantly improved mitochondrial morphological and functional abnormalities and corrected the disorders of mitochondrial dynamics. Furthermore, the protective effects of RDN against atrial remodeling were related to the regulation of mitochondrial dynamics. RDN prevented diabetes-induced atrial remodeling. These protective effects might be related to improvements in mitochondrial dynamics.

Brain injury often results in high mortality rates and significant sequelae following severe heatstroke (HS). Neuroinflammation aggravates HS-induced brain injury, yet the involvement of microglia in heat-induced neuroinflammation deserves further investigation.

Our study investigated activation status, phenotype markers, production of pro-inflammatory cytokine and reactive oxygen species (ROS) of microglia both in vitro and in vivo under HS. Utilizing high-throughput sequencing, we identified SIRT1 as a potential modulator of microglia phenotype, and observed that SIRT1 alleviated severe heatstroke-induced brain injury following intraperitoneal administration of the SIRT1 agonist SRT-1720 and the inhibitor selisistat. Additionally, the effects of SRT-1720 and selisistat on mitochondrial dynamics and microglial phenotype transition were examined in BV2 cells in vitro.

Heatstroke promotes microglia activation, as evidenced by the increased production of pro-inflammatory cytokine and reactive oxygen species. High-throughput sequencing revealed elevated expression of SIRT1 in BV2 cells under HS. Upon inhibition of SIRT1 expression, there was a corresponding increase in pro-inflammatory cytokine, iNOS, and ROS expression in BV2 cells. In vivo experiments with the SIRT1 agonist SRT-1720 showed a mitigation of neuron injury under HS, as assessed by Nissl and HE staining. Activation of SIRT1 was associated with a reduction in mitochondrial injury and a decrease in the phosphorylation of mitochondrial fission protein Drp1ser616. Furthermore, the heat-induced activation of microglia was reversed by the Drp1 inhibitor, Mdivi.

Our findings provided evidence that SIRT1 played a crucial role in inhibiting heat stress-induced microglial activation. By suppressing the phosphorylation of mitochondrial fission protein Drp1, SIRT1 contributed to the reduction of neuroinflammation and severity of heatstroke-induced brain injury.

Acute lung injury (ALI) has been a hot topic in the field of critical care research in recent years. Mitochondrial dynamics consists of mitochondrial fusion and mitochondrial fission. Dynamin-related protein 1 (Drp1), a key molecule that regulates mitochondrial fission, is important in the oxidative stress and inflammatory response to ALI. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a core protein that mediates mitochondrial biogenesis. G-protein pathway suppressor 2 (GPS2) acts as a transcriptional cofactor with regulatory effects on nuclear-encoded mitochondrial genes. This study aimed to investigate the mechanism of PGC-1α/Drp1-mediated mitochondrial dynamics involved in ALI and to demonstrate the protective mechanism of GPS2 in regulating mitochondrial structure and function and inflammation in ALI. The ALI model was constructed using LPS-induced wild-type mice and human pulmonary microvascular endothelial cells (HPMVECs). It was found that lung injury, oxidative stress and inflammation were exacerbated in the mice ALI model and that mitochondrial structure and function were disrupted in HPMVECs. In vitro studies revealed that LPS led to the upregulated expression of Drp1 and the downregulated expression of PGC-1α and GPS2. Mitochondrial division was reduced and respiratory function was restored in Drp1 knockdown cells, which inhibited oxidative stress and inflammatory response. In addition, the overexpression of PGC-1α and GPS2 significantly inhibited the expression of Drp1, mitochondrial function was restored, and inhibited reactive oxygen species (ROS) production and inflammatory factor release. Moreover, the overexpression of GPS2 promoted the upregulated expression of PGC-1α. This mechanism was also validated in vivo, in which the low expression of GPS2 in mice resulted in the upregulated expression of Drp1 and the downregulated expression of PGC-1α, and further exacerbated LPS-induced ALI. In the present study, we also found that LPS-induced the downregulated expression of GPS2 may be associated with its increased degradation by the proteasome. Therefore, these findings revealed that GPS2 inhibited oxidative stress and inflammation by modulating PGC-1α/Drp1-mediated mitochondrial dynamics to alleviate LPS-induced ALI, which may provide a new approach to the therapeutic orientation for LPS-induced ALI.

Sepsis-associated acute kidney injury (AKI) is a serious complication of systemic infection with high morbidity and mortality in patients. However, no effective drugs are available for AKI treatment. Dexmedetomidine (DEX) is an alpha 2 adrenal receptor agonist with antioxidant and anti-apoptotic effects. This study aimed to investigate the therapeutic effects of DEX on sepsis-associated AKI and to elucidate the role of mitochondrial dynamics during this process.

A lipopolysaccharide (LPS)-induced AKI rat model and an NRK-52E cell model were used in the study. This study investigated the effects of DEX on sepsis-associated AKI and the molecular mechanisms using histologic assessment, biochemical analyses, ultrastructural observation, western blotting, immunofluorescence, immunohistochemistry, qRT-PCR, flow cytometry, and si-mRNA transfection.

In rats, the results showed that administration of DEX protected kidney structure and function from LPS-induced septic AKI. In addition, we found that DEX upregulated the α2-AR/SIRT1/PGC-1α pathway, protected mitochondrial structure and function, and decreased oxidative stress and apoptosis compared to the LPS group. In NRK-52E cells, DEX regulated the mitochondrial dynamic balance by preventing intracellular Ca2+ overloading and activating CaMKII.

DEX ameliorated septic AKI by reducing oxidative stress and apoptosis in addition to modulating mitochondrial dynamics via upregulation of the α2-AR/SIRT1/PGC-1α pathway. This is a confirmatory study about DEX pre-treatment to ameliorate septic AKI. Our research reveals a novel mechanistic molecular pathway by which DEX provides nephroprotection.

Various health issues have emerged due to consuming high-fat diets (HFD), particularly the detrimental impact they have on mitochondrial dynamics and subsequet cognition functions. Specially, mitochondrial fission can serve as an upstream signal in the regulation of cortical inflammation and neural pyroptosis. Our study was designed to verify the existence of neuroinflammation in the pathogenesis of HFD-induced cognitive dysfunction and demonstrated that resveratrol (RSV) attenuated neural deficits via regulation of cortical mitochondrial fission. A total of 50 male Sprague Dawley rats were randomly divided into five groups: control (Cont, 26 weeks on normal rodent diet); high-fat diet (HFD); dietary adjustments (HFD + ND); resveratrol intervention (HFD + R); joint intervention (HFD + ND + R) for 26 weeks. The spatial learning and memory function, spine density, NLRP3 inflammasome associated protein, mRNA and protein expression involved in mitochondrial dynamics and SIRT1/PGC-1α signaling pathway in brain were measured. Furthermore, reactive oxygen species (ROS) accumulation and resultant mitochondrial membrane potential (MMP) alteration in PC12 cells exposed to palmitic acid (PA) or Drp1 inhibitor (Mdivi-1) were detected to reflect mitochondrial function. The findings suggested that prolonged treatment of RSV improved cognitive deficits and neuronal damage induced by HFD, potentially attributed to activation of the SIRT1/PGC-1α axis. We further indicated that the activation of the NLRP3 inflammasome in PA (200 μM) treated PC12 cells could be inhibited by Mdivi-1. More importantly, Mdivi-1 (10 μM) reduced intracellular ROS levels and enhanced MMP by reversing Drp1-mediated aberrant mitochondrial fission. To summarize, those results clearly indicated that a HFD inhibited the SIRT1/PGC-1α pathway, which contributed to an imbalance in mitochondrial dynamics and the onset of NLRP3-mediated pyroptosis. This effect was mitigated by the RSV possibly through triggering the SIRT1/PGC-1α axis, prevented aberrant mitochondrial fission and thus inhibited the activation of the NLRP3 inflammatory pathway.

A critical role for mitochondrial dysfunction has been shown in the pathogenesis of fibromyalgia. It is a chronic pain syndrome characterized by neuroinflammation and impaired oxidative balance in the central nervous system. Boswellia serrata (BS), a natural polyphenol, is a well-known able to influence the mitochondrial metabolism. The objective of this study was to evaluate the mitochondrial dysfunction and biogenesis in fibromyalgia and their modulation by BS. To induce the model reserpine (1 mg/Kg) was subcutaneously administered for three consecutive days and BS (100 mg/Kg) was given orally for twenty-one days. BS reduced pain like behaviors in reserpine-injected rats and the astrocytes activation in the dorsal horn of the spinal cord and prefrontal cortex that are recognized as key regions associated with the neuropathic pain. Vulnerability to neuroinflammation and impaired neuronal plasticity have been described as consequences of mitochondrial dysfunction. BS administration increased PGC-1α expression in the nucleus of spinal cord and brain tissues, promoting the expression of regulatory genes for mitochondrial biogenesis (NRF-1, Tfam and UCP2) and cellular antioxidant defence mechanisms (catalase, SOD2 and Prdx 3). According with these data BS reduced lipid peroxidation and the GSSG/GSH ratio and increased SOD activity in the same tissues. Our results also showed that BS administration mitigates cytochrome-c leakage by promoting mitochondrial function and supported the movement of PGC-1α protein into the nucleus restoring the quality control of mitochondria. Additionally, BS reduced Drp1 and Fis1, preventing both mitochondrial fission and cell death, and increased the expression of Mfn2 protein, facilitating mitochondrial fusion. Overall, our results showed important mitochondrial dysfunction in central nervous system in fibromyalgia syndrome and the role of BS in restoring mitochondrial dynamics.

Kidney stone formation is a common disease that causes a significant threat to human health. The crystallization mechanism of calcium oxalate, the most common type of kidney stone, has been extensively researched, yet the damaging effects and mechanisms of calcium oxalate crystals on renal tubular epithelial cells remain incompletely elucidated. Regulated mitochondrial dynamics is essential for eukaryotic cells, but its role in the occurrence and progression of calcium oxalate (CaOx) nephrolithiasis is not yet understood.

An animal model of calcium oxalate-related nephrolithiasis was established in adult male Sprague‒Dawley (SD) rats by continuously administering drinking water containing 1% ethylene glycol for 28 days. The impact of calcium oxalate crystals on mitochondrial dynamics and apoptosis in renal tubular epithelial cells was investigated using HK2 cells in vitro. Blood samples and bilateral kidney tissues were collected for histopathological evaluation and processed for tissue injury, inflammation, fibrosis, oxidative stress detection, and mitochondrial dynamics parameter analysis.

Calcium oxalate crystals caused higher levels of mitochondrial fission and apoptosis in renal tubular epithelial cells both in vivo and in vitro. Administration of a PPARγ agonist significantly alleviated mitochondrial fission and apoptosis in renal tubular epithelial cells, and improved renal function, accompanied by reduced levels of oxidative stress, increased antioxidant enzyme expression, alleviation of inflammation, and reduced fibrosis in vivo.

Our results indicated that increased mitochondrial fission in renal tubular epithelial cells is a critical component of kidney injury caused by calcium oxalate stones, leading to the accumulation of reactive oxygen species within the tissue and the subsequent initiation of apoptosis. Regulating mitochondrial dynamics represents a promising approach for calcium oxalate nephrolithiasis.

Mitochondrial damage is an early and key marker of neuronal damage in prion diseases. As a process involved in mitochondrial quality control, mitochondrial biogenesis regulates mitochondrial homeostasis in neurons and promotes neuron health by increasing the number of effective mitochondria in the cytoplasm. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that regulates neuronal mitochondrial biogenesis and quality control in neurodegenerative diseases via deacetylation of a variety of substrates. In a cellular model of prion diseases, we found that both SIRT1 protein levels and deacetylase activity decreased, and SIRT1 overexpression and activation significantly ameliorated mitochondrial morphological damage and dysfunction caused by the neurotoxic peptide PrP106-126. Moreover, we found that mitochondrial biogenesis was impaired, and SIRT1 overexpression and activation alleviated PrP106-126-induced impairment of mitochondrial biogenesis in N2a cells. Further studies in PrP106-126-treated N2a cells revealed that SIRT1 regulates mitochondrial biogenesis through the PGC-1α-TFAM pathway. Finally, we showed that resveratrol resolved PrP106-126-induced mitochondrial dysfunction and cell apoptosis by promoting mitochondrial biogenesis through activation of the SIRT1-dependent PGC-1α/TFAM signaling pathway in N2a cells. Taken together, our findings further describe SIRT1 regulation of mitochondrial biogenesis and improve our understanding of mitochondria-related pathogenesis in prion diseases. Our findings support further investigation of SIRT1 as a potential target for therapeutic intervention of prion diseases.