Cardiac endothelial cells are one of the main cellular components of the heart, and there is at least one capillary in the vicinity of each cardiomyocyte (Fig. 1A), snaking around each cardiomyocyte (Fig. 1B) and playing an important “plumbing” role (Fig. 1C) [2]. Endothelial dysfunction has been identified as a major mediator of cardiovascular diseases and is closely related to mitochondrial abnormalities that regulate the structure and function of endothelial cells themselves. Under conditions of oxygen-glucose deprivation/reoxygenation (OGD/R) injury, cardiac microvascular ECs (CMECs) undergo mitochondrial fission leading to cytochrome C release (cytochrome C is released from the mitochondria into the cytoplasm of the CMECs) resulting in activation of mitochondria-dependent apoptotic pathways [14]. This was evidenced by the reduced co-localization of mitochondria and cytochrome C (Fig. 1D). Meanwhile, cardiovascular illness may result in endothelial mitochondrial dysfunction, which harms endothelial cells and exacerbates cardiovascular conditions. Previous studies have shown that mitochondrial damage after myocardial infarction induces vascular inflammation further impairing cardiovascular health [17]. Acute myocardial ischemia results in oxidative damage to ECs’ mitochondria, which subsequently activate GABARAPL1-induced NLRP3 Inflammasomes via an Autophagic-Exosome Manner. The NLRP3 Inflammasomes stimulus induces the proliferation of monocytes and neutrophils, which ultimately leads to vascular inflammation [17].

Deacetylase sirtuin, ionic homeostasis, and several other factors have important effects on cardiovascular endothelial cell mitochondria. This section summarizes the mechanisms of influence and treatment related to these factors.

Mitochondria affect endothelial cell function during normal physiological processes. (A-C), Fluorescence living cell images of rat left ventricular myocardium. Endothelial cells were stained with fluorescent-labeled lectin (green) and multiphoton microscopy showed that endothelial cells meandered around and around cardiomyocytes (blue), playing an important role as “conduits” and also regulating mitochondrial activity in cardiomyocytes. (A), Low magnification illustrates the degree of myocardial vascularization. Scale bars: 100 μm. (B), Different colors from green to red represent different depths of endothelium and cardiac myocytes in blue shown at 6 μm depth. Scale bars: 20 μm. (C), Fluorescence images at high magnification, NAD(P)H autofluorescence could be detected from endothelialmitochondria (arrow). Scale bars: 10 μm. Copyright 2007, Reprinted with from permission from Wolters Kluwer Health, Inc [2]. D Under conditions of oxygen-glucose deprivation/reoxygenation (OGD/R) injury, cardiac microvascular ECs (CMECs) undergo mitochondrial fission leading to cytochrome C release, resulting in activation of mitochondria-dependent apoptotic pathways. The analysis of colocalization between mitochondria and cytochrome C was performed by immunostaining of cytochrome C (green) and Tomm20 (red). Cyt-C: cytochrome C. Scale bars: 10 μm. Copyright 2021, Reprinted with from permission from Springer Nature Publishing Group [14]. (E) Mitochondrial Ca2+ accumulation can trigger the opening of high-conductance pores and permeability transition in the inner mitochondrial membrane (IMM). Copyright 2015, Reprinted with from permission from Elsevier B.V. [15]. (F) Diagram showing the possible mechanisms of iron overload induced VEC damage. Excessive free iron ions produce excessive ROS in the cytoplasm that inhibit DDAHII and accumulate ADMA. ADMA not only competitively inhibits eNOS activity, but also induces the decoupling of eNOS to produce more ROS, which leads to a vicious cycle. In addition, excessive ROS enter mitochondria and activate RIRR mechanism, which these two cycles together induce mitochondrial dysfunction and VEC damage. Copyright 2019, Reprinted with from permission from Hindawi Publishing Group [16]

The Sirtuin family is the first discovered class III HDAC. They all possess a highly conserved nicotinamide adenine dinucleotide (NAD+) binding domain and a catalytic domain, while different N-terminal and C-terminal structures allow them to bind to different substrates [18]. SIRT1 and SIRT3 are two well-characterized cardioprotective isoforms [19]. SIRT1, as the most extensively studied star molecule in the family, participates in various mechanisms including metabolism, immune response, and aging regulation. It regulates nuclear-encoded proteins involved in mitochondrial biogenesis and can directly control the expression of mitochondrial genes. Studies have shown that overexpression of SIRT1 can prevent cardiomyocytes from suffering myocardial I/R injury-induced cell death and oxidative stress damage [20]. Furthermore, activation of the adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK)/SIRT1/peroxisome proliferator-activated receptor γ coactivator 1-alpha (PGC-1α) pathway is essential in mitigating mitochondrial oxidative stress damage [21]. The upstream regulatory protein of SIRT, AMPK, has been reported to be activated during myocardial I/R injury, exerting protective effects by regulating various metabolic pathways, including mitochondrial function [22, 23]. Specifically, AMPK activation induces SIRT1 to regulate PGC1α activity, thereby reducing mitochondrial oxidative stress damage [22]. The therapeutic drug, Xinmai’an tablets, composed of six traditional Chinese medicines, can reduce myocardial infarct size, alleviate myocardial and endothelial injury, and protect the heart by acting through the AMPK/SIRT1/PGC-1 pathway [21]. p66Shc stimulates mitochondrial ROS production through its oxidoreductase activity, while SIRT 1 negatively regulates p66Shc expression at the transcriptional level to suppress the effects of ROS, protecting ECs from oxidative damage [24]. The specific mechanism involves SIRT1 binding to the p66Shc promoter, leading to histone H3 deacetylation, thereby attenuating p66Shc transcription and translation [24]. SIRT3 serves as a primary regulator of mitochondrial energy metabolism, influencing mitochondrial respiratory function through cytochrome C (CytC) [18]. Sirt3 deficiency may result in mitochondrial protein hyperacetylation, promoting endothelial dysfunction, increasing smooth muscle cell hypertrophy, inducing vascular inflammation, and triggering age-dependent hypertension [25]. Animal experiments have shown that decreased expression of Sirt3 leads to vascular dysfunction and hypertension [26]. Recent studies have found lower levels of the mitochondrial deacetylase, sirtuin (Sirt) 3, in hypertensive patients compared to normal individuals [27].

Disruption of ionic homeostasis can lead to mitochondrial dysfunction. In recent years, increasing evidence suggests that mitochondrial dysfunction caused by mitochondrial calcium overload leads to endothelial dysfunction and cardiomyocyte apoptosis [28,29,30]. Mitochondrial Ca2+ accumulation can trigger the opening of high-conductance pores in the inner mitochondrial membrane (IMM) (Fig. 1E). This phenomenon is known as mitochondrial permeability transition (MPT). Subsequently, there is mitochondrial swelling and rupture of the mitochondrial membrane, leading to the release of mitochondrial proteins including cytochrome c into the cytosol. Angiotensin II (Ang-II) stimulates vascular endothelial cells (VECs) to secrete endothelin (ET), activating intracellular signaling pathways that open calcium ionic channels [31]. Simultaneously, Ang-II reduces the activity of Na+-K + ATPase, inhibiting the function of the Na+-K+ pump, ultimately leading to the opening of calcium ion channels and massive influx of calcium ions, resulting in calcium overload [31]. Li’s study demonstrates that tea polyphenols protect VECs from calcium overload-induced damage by enhancing mitochondrial membrane potential (MMP) and reducing endothelin production and intracellular calcium levels induced by Ang-II [31]. Another study by Li reported the protective effect of dihydromyricetin against vascular endothelial cell injury induced by angiotensin II [32]. The specific mechanism involves dihydromyricetin increasing MMP levels, reducing Ca2+ levels, and lowering AngII levels in endothelial tissue, thereby protecting VEC mitochondria and shielding VEC from AngII-induced damage [32]. In addition to Ang-II-mediated calcium overload, hyperuricemia also leads to mitochondrial calcium overload via the mitochondrial Na+/Ca2+ exchanger [33]. In terms of treatment, Li et al. reported the inhibitory mechanism of Histidine triad (HIT) nucleotide-binding protein 2 (HINT2) on mitochondrial calcium overload in CMECs [14]. HINT2 can directly interact with the mitochondrial calcium uniporter (MCU) complex in CMECs, inhibiting mitochondrial calcium overload [14]. This enhances cardiomyocyte survival rates and protects cardiac function under ischemic conditions.

In addition to calcium overload, mitochondrial iron overload can lead to mitochondrial dysfunction. Iron overload leads to mitochondrial dysfunction in endothelial cells, thereby damaging VECs. He et al. [16]. reported the mechanism by which iron overload damages endothelial mitochondria via the ROS/ADMA/DDAHII/eNOS/NO pathway (Fig. 1F). On the one hand, excessive free iron ions in the cytoplasm generate an overload of reactive oxygen species (ROS), inhibiting DDAHII and accumulating ADMA. ADMA not only competitively inhibits eNOS activity, reducing NO synthesis, but also induces eNOS uncoupling, generating more ROS, thereby establishing a vicious cycle of ROS production [16]. On the other hand, excessive ROS enter mitochondria, weakening mitochondrial membrane potential (MMP), opening the mitochondrial permeability transition pore (mPTP), activating the RIRR mechanism, forming another vicious cycle [16]. Targeting the ROS/ADMA/DDAHII/eNOS/NO pathway, Chen et al. found that Luteoloside could target endothelial cell mitochondria via the ROS/ADMA/DDAHII/eNOS/NO pathway to protect the vascular endothelium from iron overload injury [34]. Mitoferrin 2 (Mfrn2) is an iron transport protein on the inner membrane of mitochondria. Studies have shown that TNF-α increases the binding of 14-3-3 epsilon (ε) to Mfrn2, preventing the degradation of Mfrn2, leading to mitochondrial iron overload in ECs [35]. Silencing the Mfrn2 gene can inhibit TNF-α-induced mitochondrial iron overload, thereby stabilizing mitochondrial membrane potential and improving mitochondrial function [35]. The therapeutic drug, isoliquiritigenin, is a compound similar to resveratrol, possessing potent antioxidant capabilities and cardiovascular protective effects [36]. Research by Chen et al. suggests that isoliquiritigenin inhibits mitochondrial iron toxicity through the PRDX2-MFN2-ACSl4 pathway, beneficially protecting the cardiac microvasculature in diabetic patients [36].

Copper also plays a crucial role in maintaining mitochondrial function. Research indicates that homocysteine disrupts copper homeostasis in endothelial cells. Elevated homocysteine levels decrease intracellular copper concentration and lead to redistribution of copper among different molecular weight fractions, limiting its availability in higher molecular weight fractions [37]. This redistribution restricts effective utilization of copper by key molecules, resulting in reduced activity of cytochrome c oxidase (CCO), an essential component of the mitochondrial respiratory chain [37]. Additionally, levels of the copper chaperone protein COX17, closely associated with CCO, decline accordingly [37]. COX17 is responsible for delivering copper to CCO [38]. These changes ultimately lead to collapse of mitochondrial membrane potential, impairing normal mitochondrial function and causing damage to endothelial cells [37].

Zinc is commonly regarded as an antioxidant with cellular protective properties [39]. Previous studies have demonstrated the critical importance of zinc in endothelial integrity, where zinc deficiency can severely compromise endothelial barrier function [40]. Zinc ions can protect endothelial cells by inhibiting the activation of caspase-3 subunits [39]. However, recent research suggests that zinc ions not only have protective effects but can also impair mitochondrial function and induce mitochondrial autophagy in cardiomyocytes under conditions of overload [41]. Zinc ion overload leads to decreased mitochondrial membrane potential, reduced expression of Mfn2, increased levels of reactive oxygen species (ROS) in both the cytoplasm and mitochondria, resulting in mitochondrial dysfunction [41]. Zinc overload induces mitochondrial autophagy through two pathways: activation of the PINK1/Parkin signaling pathway and Mfn2-mediated ROS induction [41].

Activation of some hormone receptors also induces mitochondrial disorders leading to cardiovascular disease. Activation of histamine H2 receptors can elevate levels of phospho-extracellular signal-regulated protein kinases 1 and 2 (p-ERK1/2), Bcl-2-associated X protein (Bax), phospho-death associated protein kinase (p-DAPK2), and caspase 3, promoting myocardial mitochondrial dysfunction and increasing cardiac endothelial permeability, thus exacerbating myocardial ischemia/reperfusion (I/R) injury [42]. Activation of mineralocorticoid receptors initiates inflammation and fibrosis in the heart by increasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondrial ROS production [43].

Additionally, tissue damage frequently occurs during myocardial ischemia/reperfusion (I/R) [44]. Endothelial cells contribute to this tissue damage through the coordination of the complement cascade. Studies have shown that endothelial cell mitochondria may be a source of activated complement molecules during myocardial I/R injury [44]. The mitochondria of endothelial cells may release certain molecules that can bind to C1q molecules in the complement cascade, thereby triggering the activation of the classical complement pathway [44].

Cardiovascular and all-cause mortality rates in individuals with MetS are significantly higher than in those without MetS [45]. Animal studies have shown that MetS can cause substantial functional and structural damage to myocardial microvasculature [46]. The novel mitochondria-targeted peptide elamipretide (ELAM) targets and preserves the mitochondrial inner membrane phospholipid cardiolipin, which has been shown to have cardioprotective effects [47, 48]. Cardiolipin is an anionic phospholipid component of the mitochondrial inner membrane that plays a key role in cristae formation and mitochondrial function [49]. The peroxidation and loss of cardiolipin can activate the caspase pathway and initiate apoptosis, as well as trigger the production and release of mitochondrial reactive oxygen species [46, 50]. The study by Yuan et al. demonstrated that elamipretide (ELAM) can restore endothelial cell cardiolipin content in MetS animals (as shown in Fig. 2A), preserve coronary artery EC mitochondria, and reduce vascular damage [46].

In addition, air pollution-induced mitochondrial damage is a major risk factor for cardiovascular disease, according to a 2018 report by the World Health Organization [51]. Particulate matter (PM) in air pollution acts as pro-oxidants that generate harmful electrophilic metabolites, causing irreversible mitochondrial DNA oxidative damage, thereby damaging mitochondrial structure [52]. This structural damage can activate mitochondrial ROS production, triggering abnormal innate immune responses and promoting inflammatory reactions [53]. Furthermore, damaged mitochondria may lead to impaired oxidative phosphorylation function, triggering myocardial hypertrophy that could have serious implications for cardiovascular health [54]. The specific mechanisms associated with PM leading to mitochondrial damage are schematically shown in Fig. 2B.

Furthermore, research by Chang et al. suggests that natural antioxidants also play a crucial role in regulating mitochondrial protection of cardiovascular ECs against stress-induced damage [55]. For instance, Panax notoginseng saponins can reduce ROS-mediated oxidative damage, improve mitochondrial dysfunction, and inhibit cardiomyocyte apoptosis [56]; and Ligustrazine can ameliorate oxidative stress-induced damage in HUVECs, inhibiting the release of cytochrome C from mitochondria to the cytoplasm [57].

Mitochondrial abnormalities cause damage to the cardiovascular endothelium. (A), Metabolic syndrome (MetS) could induce mitochondrial damage in endothelial cells and Elamipretide (ELAM) restores endothelial cell cardiolipin content. Double immunofluorescent staining of endothelial marker CD31 (green) and mitochondrial markers outer membrane transferase (TOM)-20(red) and mitochondrial inner membrane phospholipids (red) shows reduced expression of endothelial mitochondria and cardiolipin (yellow combined) in metabolic syndrome (METS) and normal in ELAM treated animal models. Copyright 2018, Reprinted with from permission from American Physiological Society [46]. (B), Mechanism and process of mitochondrial dysfunction caused by particulate matter in cardiovascular diseases. The transition metals present on the surface of particulate matter are capable of generating both intracellular and extracellular ROS which causes mitochondrial dysfunction. PM: Particulate Matter, TLR4:Toll-like receptor 4, MyD88: Myeloid differentiation primary response Protein 88, TRAF6:TNF receptor associated factor 6, IKKB: Inhibitor of kappa B kinase, NF-kB: Nuclear factor kappa B, mtDNA: Mitochondrial DNA, ACS: Acute coronary syndrome, ROS: Reactive oxygen species, cGAS: Cyclic GMP-AMP synthase, cGAMP: Cyclic-GMP-AMP, STING: Stimulator of interferon genes, IRF3: Interferon regulatory Factor 3, TBK1:TANK Binding Kinase 1,MPTP: mitochondrial permeability transition pore, TLR9:Toll-like receptor 9, MAVS: Mitochondrial antiviral signaling protein, MFN-2: Mitofusin-2, NEK7: Never in mitosis genes related kinase 7, NLRP3: Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3, DNMT1:DNA methyltransferase 1, TET1: Ten-eleven translocation, eATP: Extracellular Adenosine Triphosphate, IL-18: Interleukin-18. Copyright 2018, Reprinted with from permission from Elsevier B.V [51]

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a lung disorder with limited treatment strategies and a high severity, with a mortality rate of 30–40% [58]. The mechanism of ALI/ARDS involves EC inflammation and endothelial barrier dysfunction, leading to inflammation infiltration, interstitial edema, alveolar filling, and ultimately respiratory failure [59]. Memet et al. research indicates a close association between endothelial barrier failure and increased uncoupling protein 2 (UCP2) on the mitochondrial inner membrane [60], while Dilip et al. study suggests that adiponectin (APN) deficiency can cause mitochondrial dysfunction in pulmonary ECs, leading to lung injury [61,