As a vital component of blood vessels, endothelial cells play a key role in maintaining overall physiological function by residing between circulating blood and semi-solid tissue. Various stress stimuli can induce endothelial injury, leading to the onset of corresponding diseases in the body. In recent years, the importance of mitochondria in vascular endothelial injury has become increasingly apparent. Mitochondria, as the primary site of cellular aerobic respiration and the organelle for “energy information transfer,” can detect endothelial cell damage by integrating and receiving various external stress signals. The generation of reactive oxygen species (ROS) and mitochondrial dysfunction often determine the evolution of endothelial cell injury towards necrosis or apoptosis. Therefore, mitochondria are closely associated with endothelial cell function, helping to determine the progression of clinical diseases. This article comprehensively reviews the interconnection and pathogenesis of mitochondrial-induced vascular endothelial cell injury in cardiovascular diseases, renal diseases, pulmonary-related diseases, cerebrovascular diseases, and microvascular diseases associated with diabetes. Corresponding therapeutic approaches are also provided. Additionally, strategies for using clinical drugs to treat vascular endothelial injury-based diseases are discussed, aiming to offer new insights and treatment options for the clinical diagnosis of related vascular injuries.

Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPR^mt) are the predominant stress-responsive and protective mechanisms involved in repairing damaged mitochondria. Although mitochondrial homeostasis requires the coordinated actions of mitophagy and UPR^mt, their molecular basis and interactive actions are poorly understood in sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac dysfunction and mitochondrial damage. Although both mitophagy and UPR^mt were slightly activated by LPS in cardiomyocytes, their endogenous activation failed to prevent sepsis-mediated myocardial injury. However, administration of urolithin A, an inducer of mitophagy, obviously reduced sepsis-mediated cardiac depression by normalizing mitochondrial function. Interestingly, this beneficial action was undetectable in cardiomyocyte-specific FUNDC1 knockout (FUNDC1^CKO) mice. Notably, supplementation with a mitophagy inducer had no impact on UPR^mt, whereas genetic ablation of FUNDC1 significantly upregulated the expression of genes related to UPR^mt in LPS-treated hearts. In contrast, enhancement of endogenous UPR^mt through oligomycin administration reduced sepsis-mediated mitochondrial injury and myocardial dysfunction; this cardioprotective effect was imperceptible in FUNDC1^CKO mice. Lastly, once UPR^mt was inhibited, mitophagy-mediated protection of mitochondria and cardiomyocytes was partly blunted. Taken together, it is plausible that endogenous UPR^mt and mitophagy are slightly activated by myocardial stress and they work together to sustain mitochondrial performance and cardiac function. Endogenous UPR^mt, a downstream signal of mitophagy, played a compensatory role in maintaining mitochondrial homeostasis in the case of mitophagy inhibition. Although UPR^mt activation had no negative impact on mitophagy, UPR^mt inhibition compromised the partial cardioprotective actions of mitophagy. This study shows how mitophagy modulates UPR^mt to attenuate inflammation-related myocardial injury and suggests the potential application of mitophagy and UPR^mt targeting in the treatment of myocardial stress.

This study investigated the mechanism by which NR4A1 regulates mitochondrial fission factor (Mff)-related mitochondrial fission and FUN14 domain 1 (FUNDC1)-mediated mitophagy following cardiac ischemia-reperfusion injury(I/R). Our findings showed that the damage regulation was positively correlated with the pathological fission and pan-apoptosis of myocardial cell mitochondria. Compared with wild-type mice (WT), NR4A1-knockout mice exhibited resistance to myocardial ischemia-reperfusion injury and mitochondrial pathological fission, characterized by mitophagy activation. Results showed that ischemia-reperfusion injury increased NR4A1 expression level, activating mitochondrial fission mediated by Mff and restoring the mitophagy phenotype mediated by FUNDC1. The inactivation of FUNDC1 phosphorylation could not mediate the normalization of mitophagy in a timely manner, leading to an excessive stress response of unfolded mitochondrial proteins and an imbalance in mitochondrial homeostasis. This process disrupted the normalization of the mitochondrial quality control network, leading to accumulation of damaged mitochondria and the activation of pan-apoptotic programs. Our data indicate that NR4A1 is a novel and critical target in myocardial I/R injury that exertsand negative regulatory effects by activating Mff-mediated mito-fission and inhibiting FUNDC1-mediated mitophagy. Targeting the crosstalk balance between NR4A1-Mff-FUNDC1 is a potential approach for treating I/R.

Background: Septic cardiomyopathy (SCM), a common cardiovascular comorbidity of sepsis, has emerged among the leading causes of death in patients with sepsis. SCM’s pathogenesis is strongly affected by mitochondrial metabolic dysregulation and immune infiltration disorder. However, the specific mechanisms and their intricate interactions in SCM remain unclear. This study employed bioinformatics analysis and drug discovery approaches to identify the regulatory molecules, distinct functions, and underlying interactions of mitochondrial metabolism and immune microenvironment, along with potential interventional strategies in SCM.Methods: GSE79962, GSE171546, and GSE167363 datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and module genes were identified using Limma and Weighted Correlation Network Analysis (WGCNA), followed by functional enrichment analysis. Machine learning algorithms, including support vector machine–recursive feature elimination (SVM–RFE), least absolute shrinkage and selection operator (LASSO) regression, and random forest, were used to screen mitochondria-related hub genes for early diagnosis of SCM. Subsequently, a nomogram was developed based on six hub genes. The immunological landscape was evaluated by single-sample gene set enrichment analysis (ssGSEA). We also explored the expression pattern of hub genes and distribution of mitochondria/inflammation-related pathways in UMAP plots of single-cell dataset. Potential drugs were explored using the Drug Signatures Database (DSigDB). In vivo and in vitro experiments were performed to validate the pathogenetic mechanism of SCM and the therapeutic efficacy of candidate drugs.Results: Six hub mitochondria-related DEGs [MitoDEGs; translocase of inner mitochondrial membrane domain-containing 1 (TIMMDC1), mitochondrial ribosomal protein S31 (MRPS31), F-box only protein 7 (FBXO7), phosphatidylglycerophosphate synthase 1 (PGS1), LYR motif containing 7 (LYRM7), and mitochondrial chaperone BCS1 (BCS1L)] were identified. The diagnostic nomogram model based on the six hub genes demonstrated high reliability and validity in both the training and validation sets. The immunological microenvironment differed between SCM and control groups. The Spearman correlation analysis revealed that hub MitoDEGs were significantly associated with the infiltration of immune cells. Upregulated hub genes showed remarkably high expression in the naive/memory B cell, CD14⁺ monocyte, and plasma cell subgroup, evidenced by the feature plot. The distribution of mitochondria/inflammation-related pathways varied across subgroups among control and SCM individuals. Metformin was predicted to be the most promising drug with the highest combined score. Its efficacy in restoring mitochondrial function and suppressing inflammatory responses has also been validated.Conclusions: This study presents a comprehensive mitochondrial metabolism and immune infiltration landscape in SCM, providing a potential novel direction for the pathogenesis and medical intervention of SCM.

Vascular endothelial cells, serving as a barrier between blood and the arterial wall, play a crucial role in the early stages of the development of atherosclerosis, cardiovascular diseases (CVDs), and Alzheimer’s disease (AD). Mitochondria, known as the powerhouses of the cell, are not only involved in energy production but also regulate key biological processes in vascular endothelial cells, including redox signaling, cellular aging, calcium homeostasis, angiogenesis, apoptosis, and inflammatory responses. The mitochondrial quality control (MQC) system is essential for maintaining mitochondrial homeostasis. Current research indicates that mitochondrial dysfunction is a significant driver of endothelial injury and CVDs. This article provides a comprehensive overview of the causes of endothelial injury in CVDs, ischemic stroke in cerebrovascular diseases, and AD, elucidating the roles and mechanisms of mitochondria in these conditions, and aims to develop more effective therapeutic strategies. Additionally, the article offers treatment strategies for cardiovascular and cerebrovascular diseases, including the use of clinical drugs, antioxidants, stem cell therapy, and specific polyphenols, providing new insights and methods for the clinical diagnosis and treatment of related vascular injuries to improve patient prognosis and quality of life. Future research should delve deeper into the molecular and mechanistic links between mitochondrial abnormalities and endothelial injury, and explore how to regulate mitochondrial function to prevent and treat CVDs.

Doxorubicin (DOX) demonstrates significant therapeutic and anticancer efficacy. Nevertheless, it demonstrates significant cardiotoxicity, resulting in permanent cardiac damage. Ligustrazine (LIG) is a bioactive alkaloid derived from the rhizome of the medicinal plant Ligusticum chuanxiong Hort. The alkaloid has exhibited cardioprotective properties. The therapeutic application of LIG is constrained by inadequate water solubility, fast breakdown, and low bioavailability. Nanoparticle drug delivery technologies effectively address these constraints by encapsulating LIG into nanocarriers, significantly enhancing its solubility and bioavailability, hence maximizing its therapeutic efficacy. Consequently, this study employed tetrahedral backbone nucleic acid molecules as LIG carriers. Furthermore, animal models and single-cell sequencing analyses were employed to forecast the mechanisms and targets of pertinent studies. A mouse model genetically modified for the piezo type mechanosensitive ion channel component 1 (PIEZO1), transmembrane BAX inhibitor motif containing 6 (TMBIM6), and prohibitin 2 (PHB2), along with an in vivo and in vitro model of DOX-induced cardiomyopathy (DIC), was established, and a gene-modified cellular system comprising upstream genes and downstream effector targets was constructed. The mechanism of LIG was validated by molecular biology and integrated pharmacology with the implementation of the LIG nano-drug loading method. LIG nano-delivery enhanced DOX-induced cardiac dysfunction and mitochondrial impairment by modulating the PHB2Ser91/Ser176 phosphorylation axis through PIEZO1-TMBIM6, and significantly suppressed cardiomyocyte pyroptosis resulting from mitochondrial homeostasis dysregulation. The findings indicate that LIG nano-delivery is a promising therapeutic approach for addressing DIC. The PHB2Ser91/Ser176 phosphorylation axis regulated by PIEZO1-TMBIM6 is an important target for LIG nano-drug delivery systems to improve mitochondrial damage in DIC.