Cardiovascular disease (CVD) is primarily initiated by the development of atherosclerosis, the thickening and hardening of arteries caused by plaque build-up in the inner arterial lining [1]. Atherosclerosis is characterized by lipid and fibrous element accumulation in the large arteries and begins with endothelial dysfunction succeeded by an inflammatory reaction and foam cell formation [2,3].

Endothelial dysfunction is caused by various factors; however, mitochondrial dysfunction is the primary cause and a key contributor to CVD [4]. Mitochondrial dysfunction can cause reactive oxygen species (ROS) accumulation, energy stress, and cell death [5]. Endothelial−mitochondrial dysfunction can be caused by various factors including oxidative stress, inflammation, and aging [6]. Related mechanisms include impaired oxidative phosphorylation, increased ROS production, apoptosis, inflammation, and mitophagy [7-11]. Endothelial−mitochondrial dysfunction can be detected early and may serve as a biomarker for early coronary artery disease detection. Targeting mitochondrial ROS and oxidative stress may be a potential therapeutic strategy for treating endothelial dysfunction and CVD.

PTEN-induced protein kinase 1 (PINK1) plays a pivotal role in controlling the mitochondrial quality. It functions as a sensor of mitochondrial damage and activates mitochondrial quality control (MQC) pathways in response to mitochondrial damage [12,13]. PINK1 can be used to detect mitochondrial damage because it rapidly accumulates and activates in the presence of mitochondrial stressors [14]. In this review, we discuss the endothelial dysfunction, which can induce early atherosclerosis, in CVD pathogenesis and the potential of PINK1-derived mitophagy to overcome this concern.

MQC ensures proper functioning of mitochondria, which are responsible for cellular energy production. MQC involves the coordination of various processes, including proteostasis, biogenesis, dynamics, and mitophagy [15]. Mitophagy involves the targeted elimination of impaired mitochondria through autophagosomes, followed by their breakdown via lysosomes. The mitophagy pathway involves PINK1 and the E3 ubiquitin ligase Parkin [16-18].

PINK1 is involved in all tiers of MQC, including mitochondrial stabilization, chaperone phosphorylation, and mitochondrial network regulation [19]. PINK1 promotes Parkin recruitment to the mitochondrial outer membrane (MOM) for ubiquitinating the MOM proteins with canonical and noncanonical ubiquitin chains [20,21]. PINK1 is also involved in the production of mitochondria-derived vesicles, which removes localized patches of mitochondrial damage [22,23]. The role of PINK1 in MQC is important for preventing various diseases, including CVD, because PINK1 is associated with mitophagy and the process of removing damaged mitochondria. Thus, PINK1 dysfunction can lead to an imbalance in mitophagy, affecting various cell types in the cardiovascular system. This imbalance has been linked to aggravation of atherosclerosis and vascular calcification (VC). Current studies suggest that the involvement of PINK1 and mitophagy in cardiovascular pathologies should be further explored and may offer new insights into disease mechanisms and treatment strategies (Fig. 1) [24].

Figure 1. PTEN-induced protein kinase 1 (PINK1)-mediated mitophagy impairment causes dysfunction of endothelial cells, vascular smooth muscle cells (VSMCs), and cardiomyocytes and develops atherosclerosis. PINK1 dysregulation directly contributes to the pathological mechanisms underlying cardiovascular diseases. The diagram shows an imbalance in mitophagy due to PINK1 dysfunction in vascular endothelial cells, smooth muscle cells, and cardiomyocytes, and the aggravation of atherosclerosis and vascular calcification. ROS, reactive oxygen species.

Mitochondrial dysfunction is a well-known hallmark of heart diseases, including ischemic heart disease (IHD) [25]. Ischemic damage can cause hypoxia and hypoxia-inducible factor (HIF)-1α expression increases in response, thereby activating hypoxia-related mechanisms. According to a recent report, HIF-1α expression significantly decreases after surgery in patients with peripheral arterial disease (PAD) who underwent revascularization procedure compared to that before surgery. Thus, HIF-1α may act as a surrogate marker in revascularization procedure in patients with PAD [26]. Mitochondria generate adenosine triphosphate (ATP) through oxidative phosphorylation, while simultaneously producing ROS. Excess ROS leads to mitochondrial dysfunction and eventual cell death [27]. Factors contributing to mitochondrial disorders in IHD include mitophagy dysregulation, increased ROS levels, and mitochondria-associated inflammation [28].

In IHD, mitochodrial dysfunction not only diminishes ATP production consequently further reducing contractile function and increasing cell death [29], but it also increase ROS production, inducing oxidative stress and damage to cellular components [25]. Moreover, mitophagy dysregulation can lead to damaged mitochondria accumulation, which can cause inflammation, oxidative stress, and cell death [30].

Therapeutic strategies for IHD involve targeting mitochondrial dysfunction. Drugs that focus on mitochondrial ion channels, such as the mitochondrial ATP-sensitive potassium channel, exhibit cardioprotective effects in IHD [31]. PINK1/Park6 are essential for normal heart function and PINK1/Parkin-mediated mitophagy plays a crucial role in maintaining cardiomyocyte homeostasis [32,33]. Additionally, acacetin protects against cardiac senescence by stimulating the PINK1/Parkin pathway and increasing LC3II, which are critical components of mitophagy [34].

In summary, PINK1 is an important kinase for maintaining normal cardiac functions, including cardiomyocyte homeostasis. Its essential role in mitophagy regulation and maintenance is pivotal, especially considering that mitochondrial dysfunction is a key factor in the development of IHD. Therapeutic strategies for IHD include targeting mitochondrial dysfunction using drugs and exercise.

Accumulated mitochondrial damage can lead to endothelial dysfunction, characterized by reduced nitric oxide bioavailability, increased oxidative stress, and inflammation [6]. Endothelial dysfunction contributes to the development of atherosclerosis, frequently found in patients with PAD. The level of hemostatic markers of endothelial dysfunction is altered and coagulation factor activity is increased in patients with PAD [35]. Plaque formation is fatal to the disease. However, it is difficult to noninvasively differentiate between plaques and thrombi in patients with PAD. Recent studies have shown that these two tissues can be differentiated non-invasively using ultrasound vascular elastography [36]. Nonetheless, endothelial dysfunction is critical in the progression of most CVD, including PAD.

Atherosclerosis is characterized by DNA damage, inflammation, cellular senescence, and apoptosis, all of which are caused by mitochondrial dysfunction [37]. To address this dysfunction, targets that can activate mitophagy are required. PINK1 expression is crucial for the activation of mitophagy. Several potential therapeutic targets of mitophagy in atherosclerosis have been identified in recent research studies.

PINK1-mediated mitophagy induction has demonstrated the ability to reduce ROS production and attenuate NOD-, LRR-, and pyrin domain-containing protein 3 inflammatory vesicle activation in endothelial cells (ECs), thereby slowing atherosclerosis progression [38]. Wu et al. [39] observed elevated PINK1 and Parkin levels in the vascular walls of obese and diabetic mice. Overall, the PINK1–Parkin pathway is activated in response to metabolic stress, thus preserving mitochondrial integrity and preventing endothelial injury. Initiating PINK1-mediated mitophagy plays a role in eliminating impaired mitochondria in vascular ECs exposed to copper oxide nanoparticles [40]. Chen et al. [41] reported that melatonin mitigates tert-butyl hydroperoxide-induced damage in ECs by boosting activated protein kinase alpha phosphorylation, facilitating the nuclear translocation of transcription factor EB, as well as increasing LC3, Parkin, and PINK1 protein expression, while reducing p62 levels. In contrast, low-density lipoprotein (LDL) oxidation elevates nuclear receptor subfamily 4 group A member 1 (NR4A1) expression in aortic ECs. This heightened NR4A1 level leads to the abnormal overactivation of PINK1–Parkin-mediated mitophagy. Excessive mitophagy subsequently causes a significant reduction in mitochondrial count and widespread endothelial apoptosis, contributing to atherosclerosis progression due to inadequate energy supply [42]. The latest studies on various reported PINK1 targets are summarized in Table 1.

Table 1 . Recent research trends targeting PTEN-induced protein kinase 1 (PINK1)-mediated mitophagy.

Gene/genetic aspect	Effect on PINK1 and mitophagy	Reference
PINK1 and Parkin levels in obese/diabetic mice	- Increased levels of PINK1 and Parkin observed in the vascular walls of obese and diabetic mice
PINK1–Parkin pathway	- Activates in response to metabolic stress - Preserves mitochondrial integrity - Prevents endothelial injury	[39]
Copper oxide nanoparticle-induced mitophagy	- Activation of PINK1-mediated mitophagy contributes to the removal of damaged mitochondria in copper oxide nanoparticle-induced vascular ECs	[40]
Melatonin intervention	- Melatonin reverses EC damage caused by tert-butyl hydroperoxide - Enhances the phosphorylation of AMPKα - Promotes transcription factor EB nuclear translocation - Upregulates the protein levels of LC3, Parkin, and PINK1 - Decreases p62	[41]

NR4A1, nuclear receptor subfamily 4 group A member 1; AMPKα, Adenosine monophosphate-activated protein kinase alpha..

Vascular smooth muscle cells (VSMCs) play a crucial role in maintaining the stability of advanced lesion plaques in atherosclerosis [43]. Nevertheless, VSMC apoptosis within these plaques leads to significant fibrous cap thinning, collagen and matrix depletion, cellular debris build-up, and heightened inflammation in the intimal region [44]. Moreover, VSMC apoptosis correlates with numerous adverse outcomes of atherosclerosis, such as plaque rupture, vascular restructuring, coagulation abnormalities, inflammatory responses, and calcification [45].

Mitophagy, a crucial process in controlling VSMC function, characteristics, longevity, and apoptosis, becomes impaired in atherosclerosis. This impairment accelerates cellular aging by increasing the levels of senescence-associated proteins and promotes the development of neointima and diet-induced atherogenesis [46]. Oxidized LDLs (oxLDLs) demonstrate several atherogenic characteristics such as promoting foam cell formation, eliciting inflammatory reactions, reducing cell proliferation, and increasing apoptosis [47]. OxLDLs suppress mitochondrial function in VSMCs by reducing respiratory activity and ATP synthesis and triggering VSMC proliferation, migration, and neointima formation in atherosclerosis [48].

PINK1 or Parkin overexpression protects against oxLDL-induced apoptosis in VSMCs, suggesting that mitophagy protects against oxLDL-induced VSMC mortality [49]. OxLDLs impair mitochondrial function in VSMCs by promoting cell proliferation and apoptosis, whereas mitophagy activation protects against cell death.

VC is a growing burden on aging societies worldwide and closely associated with many cardiovascular events and mortality. Alterations in mitochondrial function resulting from mitochondrial dysfunction, oxidative stress, calcium overload, autophagy, apoptosis, and mitochondrial DNA (mtDNA) damage can influence VSMC calcification progression [50]. Recent studies have focused on targeting mitophagy to treat VC, a representative lesion in atherosclerosis. Mitophagy, a form of autophagy, selectively removes dysfunctional and depolarized mitochondria to maintain mitochondrial function and cellular homeostasis [51].

Zhu et al. [52] reported that lactate accelerated calcification in VSMCs by suppressing BNIP3-mediated mitophagy. This suggests that lactate fosters a shift toward an osteoblastic phenotype in VSMCs and enhances calcium deposition, partially due to oxidative stress and apoptosis resulting from a deficiency in BNIP3-mediated mitophagy [52]. Moreover, the NR4A1/DNA-dependent protein kinase catalytic subunit (DNA-PKcs)/p53 pathway contributes to the process by which lactate accelerates VC, partially via increased Drp-mediated mitochondrial fission and BNIP3-associated mitophagy deficiency [53]. A recent study has reported that lactate enhances VSMC calcification via PARP1 signaling. Lactate also upregulates uncoupling protein 2 through the PARP1/POLG pathway, leading to excess Drp1-driven mitochondrial fission and PINK/Parkin-mediated mitophagy inhibition [54].

Researchers should explore interventions targeting lactate-induced mechanisms, such as BNIP3-mediated mitophagy and NR4A1/DNA-PKcs/p53 pathway, to mitigate VC. In addition, investigating the specific role of PARP1 in promoting VSMC calcification and exploring strategies to modulate its activity may offer new avenues for therapeutic development. Understanding the molecular pathways involved in lactate-induced VC may facilitate targeted interventions to prevent or alleviate this pathological process.

Several medications and natural chemicals have been shown to alter mitophagy and slow the progression of atherosclerosis. The combination of rivaroxaban and aspirin may increase PINK1 and Parkin expressions, restore mitochondrial membrane potential (ΔΨm), and decrease the ROS level in high-glucose-induced ECs [55,56]. Scutellarin, derived from a plant extract, enhances mitophagy by activating the PINK1/Parkin signaling pathway, which helps ameliorate hyperglycemia-induced endothelial injury [57]. Furthermore, resveratrol diminishes hyperglycemia-induced endothelial injury by augmenting BNIP3-linked mitophagy [58]. External hydrogen sulfide application could potentially shield aortic ECs from the harmful effects of elevated glucose and palmitate levels. This protection may occur by suppressing cell death and reducing oxidative stress while simultaneously enhancing mitophagy. This is achieved through PINK1/Parkin signaling pathway activation [59]. Curcumin is a natural polyphenol that induces mitophagy; improves mitochondrial function in CVD; reduces oxidative stress, inflammation, and apoptosis; and improves endothelial function [60]. Epigallocatechin gallate (EGCG) stimulated autophagy in ECs. Green tea polyphenol EGCG offers cardiovascular benefits by promoting autophagy through a CaMKKβ-mediated pathway, facilitating lipid droplet degradation. These findings suggest that EGCG manages ectopic lipid build-up by enhancing autophagic flux, indicating its potential as a therapeutic agent to mitigate cardiovascular complications [61].

Thus, encouraging mitophagy safeguards mitochondrial integrity and shields ECs from damage caused by elevated glucose and lipid levels. Currently, several clinical trials are targeting mitochondrial dysfunction in patients with CVD. However, most current research is still in the preclinical stage and no clinical trials have yet been completed. The relevant clinical trials are presented in Table 2.

Table 2 . Clinical trial for cardiovascular diseases related to mitochondrial dysfunction.

NCT number	Study title	Conditions	Interventions
NCT06003855	Oxygen-guided supervised exercise therapy	PAD	Behavioral: supervised exercise therapy
NCT03980548	Targeting mitochondrial fusion and fission to prevent atherosclerosis: getting the balance right	CAD patients	Procedure: CABG
NCT02434783	The relationship between PAD and mitochondrial respiratory capacity	Intermittent claudication
NCT02538900	Low in tensity exercise intervention in PAD	PAD	Behavioral: exercise/other: attention control
NCT03493412	Effects of tetrahydrobiopterin (BH4) on leg blood flow and exercise capacity in patients with PAD	PAD	Drug: sapropterin dihydrochloride (BH4)/drug: placebo
NCT02834351	Tissue lesions in exercise related ischemia	Ischemia/PAD	Other: muscle biopsy
NCT02636283	Use of entresto sacubitril/valsartan for the treatment of PAD	PAD	Drug: entresto/drug: placebo group
NCT03506633	Impacts of mitochondrial-targeted antioxidant on PAD patients	PAD	Dietary_supplement: MitoQ
NCT05708547	Role of mitophagy in myeloid cells during coronary atherosclerosis	Coronary atherosclerosis	Biological: blood samples/procedure: myocardial tissue samples/other: data collection
NCT05624125	Beetroot juice to reverse functional impairment in PAD	PAD	Other: beetroot juice/other: placebo
NCT01970332	Mechanisms that produce the leg dysfunction of claudication & treatment strategies	PAD	Procedure: revascularization surgery/other: supervised exercise therapy
NCT03965520	Exercise test and sequential training strategies in PAD	PAD	Behavioral: exercise rehabilitation by near-infrared spectrometer
NCT04377126	Unacylated ghrelin to improve functioning in PAD	PAD	Drug: ghrelin/drug: placebo
NCT05813171	The effects of allicor on patients after revascularization treatment during a year	Atherosclerosis/PAD	Dietary_supplement: allicor/drug: placebo
NCT01407172	Hydrogen sulfide and PAD	PAD
NCT04228978	Promote weight loss in obese PAD patients to prevent mobility loss	PAD/overweight or obesity	Behavioral: weight loss/behavioral: exercise
NCT02842424	Ramipril treatment of claudication	PAD	Drug: ramipril
NCT05644158	Mitochondrial function in PAD	PAD/cardiovascular diseases	Procedure: revascularization/other: exercise therapy

NCT, National Clinical Trial; PAD, peripheral artery disease; CAD, coronary artery disease; CABG, coronary artery bypass grafting..

We elucidated the pivotal role of PINK1 in mitigating mitochondrial dysfunction, thereby offering a potential therapeutic strategy for CVD. This review highlights the intricate interplay between MQC and CVD pathogenesis and emphasizes the significance of PINK1-mediated mitophagy. Exploring the effect of PINK1 on cardiomyocyte homeostasis in IHD underscores its essential role in preventing excessive ROS production and inflammation. The therapeutic potential of PINK1 activation, as exemplified by acacetin, suggests promising avenues for managing cardiac senescence. This review focuses on endothelial dysfunction in atherosclerosis, emphasizing the potential of inducing PINK1-mediated mitophagy to alleviate oxidative stress and inflammation, which are key contributors to atherosclerotic progression. However, imbalances such as overactivated mitophagy in response to specific stimuli may exacerbate atherosclerosis. The protective role of mitophagy against oxLDL-induced apoptosis in VSMCs was highlighted, emphasizing the potential therapeutic impact of PINK1 overexpression. Finally, this review focuses on VC, offering insights into lactate-induced mechanisms and PARP1 involvement. Medications and natural compounds such as rivaroxaban, scutellarin, resveratrol, hydrogen sulfide, curcumin, and EGCG are promising in modulating mitophagy to alleviate CVD progression. This comprehensive exploration emphasizes the intricate interplay between mitochondrial dysfunction, PINK1-mediated mitophagy, and potential therapeutic interventions in the complex CVD landscape.

We thank the Asan Medical Center for their support and assistance with instrumentation.

This research was supported by a National Research Foundation of Korea (NRF) grant (RS-2023-00271879).

Jun Gyo Gwon has been the managing editor of VSI since 2023. he was not involved in the review process. Otherwise, no potential conflict of interest relevant to this article was reported.

Concept and design: JGG. Analysis and interpretation: JGG. Data collection: SML. Writing the article: SML. Critical revision of the article: SML. Final approval of the article: all authors. Statistical analysis: none. Obtained funding: none. Overall responsibility: SML.