Mitochondrial permeability transition in the diabetic heart: contributions of thiol redox state and mitochondrial calcium to augmented reperfusion injury

Mitochondria from diabetic hearts are sensitized to mitochondrial permeability transition pore (PTP) opening, which may be responsible for the increased propensity for cardiac injury in diabetic hearts. The purpose of this study was to determine if redox-dependent PTP opening contributes to augmented injury in diabetic hearts, and if compounds targeted at mitochondrial PTP, ROS, and calcium influx protected diabetic hearts from injury. Hearts from control or streptozotocin-induced diabetic rats were excised for either whole-heart or isolated mitochondria experiments. Myocardial glutathione content was oxidized in diabetic hearts when compared to control, and this translated to increased oxidation of the adenine nucleotide translocase in diabetic hearts. Diabetic mitochondria displayed significantly greater sensitivity to PTP opening than non-diabetic counterparts, which was reversed with the thiol-reducing agent dithiothreitol. The thiol-oxidant diamide increased calcium sensitivity in control, but not diabetic mitochondria. Diabetic animals treated with the mitochondria-targeted ROS suppressing peptide MTP-131 also showed improved resistance to PTP opening. In separate experiments hearts underwent ex vivo ischemia/reperfusion (IR). Diabetic hearts were more susceptible to IR injury, with infarct sizes of 60 ± 4% of the area-at-risk (vs. 46 ± 2% in non-diabetics; P<0.05). Administration of the PTP blocker NIM811 (5 μM), MTP-131 (1 nM) or the mitochondrial calcium uniporter blocker minocycline (1 μM) at the onset of reperfusion reduced infarct sizes in both control and diabetic hearts. These findings suggest that augmented susceptibility to injury in the diabetic heart is mediated by redox-dependent shifts in PTP opening, and that three novel mitochondria-targeted agents administered at reperfusion may be suitable adjuvant reperfusion therapies to attenuate injury in diabetic patients.     

Mitochondrial Ca2+ uptake during simulated ischemia does not affect permeability transition pore opening upon simulated reperfusion

OBJECTIVE: Reenergization of ischemic cardiomyocytes may be associated with acute necrotic cell death due in part to cytosolic Ca2+ overload and opening of a permeability transition pore (PTP) in mitochondria. It has been suggested that Ca2+ overload during ischemia primes mitochondria for PTP opening during reperfusion. We investigated the ability of mitochondria to uptake Ca2+ during simulated ischemia (SI) and whether this uptake determines PTP opening and cell death upon simulated reperfusion (SR). METHODS: Rat heart mitochondria were submitted to either hypoxia (anoxic chamber) or to SI (respiratory inhibition, substrate depletion and acidosis) and subsequent SR. Mitochondrial Ca2+ uptake was monitored using Ca2+ microelectrodes after exposure to different [Ca2+] up to 25 microM during SI, and PTP opening was assessed by quantification of mitochondrial swelling (changes in absorbance rate at 540 nm) and calcein release. Mitochondrial Ca2+ uptake (Rhod-2 fluorescence) and cytosolic Ca2+ rise (Fura-2 ratio fluorescence) were further investigated in HL-1 cardiac myocytes submitted to SI/SR, and the effect of reducing mitochondrial Ca2+ load (with 25 microM ruthenium red) or blocking PTP opening (with 0.5 microM cyclosporin A) on the rate of cell death was investigated in adult cardiomyocytes exposed to SI/SR. RESULTS: SI induced a progressive dissipation of mitochondrial membrane potential (TMRE fluorescence); however, prior to the completion of depolarization, high levels of Ca2+ uptake were observed in mitochondria. SR induced PTP opening but this phenomenon was not influenced by the magnitude of mitochondrial Ca2+ uptake during previous SI. Blockade of the mitochondrial Ca2+ uniporter during SI in cardiomyocytes attenuated mitochondrial Ca2+ uptake but increased cytosolic Ca2+ overload and cell death upon subsequent SR. CONCLUSION: Mitochondrial Ca2+ uptake during SI buffers cytosolic Ca2+ overload but its magnitude appears not to be an important determinant of PTP opening upon subsequent SR.     

Lethal myocardial reperfusion injury: a necessary evil?

Despite being the most effective means of limiting infarct size, coronary reperfusion comes at a price and induces additional damage to the myocardium. Lethal reperfusion injury (death of myocytes that were viable at the time of reperfusion) is an increasingly acknowledged phenomenon. There are many interconnected mechanisms involved in this type of cell death. Calcium overload (generating myocyte hypercontracture), rapid recovery of physiological pH, neutrophil infiltration of the ischemic area, opening of the mitochondrial permeability-transition-pore (PTP), and apoptotic cell death are among the more important mechanisms involved in reperfusion injury. The activation of a group of proteins called reperfusion injury salvage kinases (RISK) pathway confers protection against reperfusion injury, mainly by inhibiting the opening of the mitochondrial PTP. Many interventions have been tested in human trials triggered by encouraging animal studies. In the present review we will explain in detail the main mechanism involved in reperfusion injury, as well as the various approaches (pre-clinical and human trials) performed targeting these mechanisms. Currently, no intervention has been consistently shown to reduce reperfusion injury in large randomized multicenter trials, but the research in this field is intense and the future is highly promising.     

Hydrophilic bile salt ursodeoxycholic acid protects myocardium against reperfusion injury in a PI3K/Akt dependent pathway

The opening of mitochondrial permeability transition pore (PTP) during reperfusion injury of heart has been well demonstrated and thus controlling PTP would attenuate the myocardial damage and cell death. Ursodeoxycholic acid (UDCA) is a hydrophilic bile salt and has been shown to prevent apoptosis in hepatocytes by inhibiting the opening of PTP. Here we demonstrate the role of UDCA in preventing the reperfusion injury of heart through its ability to inhibit PTP. Wistar rats underwent 30 min left coronary artery occlusion (LCA) followed by 180 min reperfusion after treatment with 40 mg/kg per iv infusion of UDCA over 30 min before LCA occlusion. Other groups of rats were treated with PTP agonist atractyloside(5 mg/kg) or PI3 kinase inhibitor wortmannin (16 ug/kg) before UDCA treatment. UDCA treatment prior to LCA occlusion, activated phosphorylation of Akt and Bad. Phosphorylating Bad prevented its translocation in to mitochondria, there by preventing the down regulation of Bcl-2 expression and PTP opening. This was confirmed by reduced cytochrome C release from intramitochondrial space in to the cytosol and hence reduced cell death either by apoptosis (4.8 vs 11.8%, P<0.001, UDCA treated against control group) or necrosis (reduced MI area in UDCA treated group (22.1%) compared to control group(46.4%), P<0.001). In contrast, inhibition of Akt activation with PI3K inhibitor wortmannin or opening the PTP with atractyloside abolished, UDCA mediated cytoprotective effects. Studies on primary culture cardiomyocytes also confirmed our in vivo results of UDCA on cell survival. These results altogether demonstrate that UDCA protect the heart against reperfusion injury by inhibiting the PTP in a PI3K/Akt dependent pathway.     

NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition

AIMS: The possible contribution of the cardiac mitochondrial permeability transition pore (PTP) towards the cardioprotective effects of Na(+)-H(+) exchanger-1 (NHE-1) inhibition was studied in hearts subjected to ischaemia/reperfusion (IR). METHODS AND RESULTS: Langendorff-perfused rat hearts were subjected to 40 min of global ischaemia and 60 min of reperfusion in the presence or absence of the NHE-1 specific inhibitor AVE-4890 (AVE, 5 microM). Mitochondrial PTP opening was determined in the intact heart using 2-deoxy-[(3)H]-glucose entrapment and in isolated mitochondria by monitoring the decrease of the calcium-induced light scattering. Mitochondrial respiration was measured with a Clark-type oxygen electrode whereas release of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) and levels of cleaved poly-(ADP-ribose) polymerase (PARP) were analysed by western blotting. IR induced mitochondrial PTP opening, which was inhibited by 28% (P < 0.05) with AVE treatment. Mitochondria isolated from AVE-treated hearts demonstrated significantly less calcium-induced swelling and higher substrate oxidation at complex I and II as well as cytochrome c oxidase and citrate synthase activity. AVE treatment also suppressed IR-induced release of AIF and EndoG from mitochondria, prevented the IR-induced rise in cleaved PARP levels, and was associated with significantly enhanced postischaemic recovery of left ventricular developed pressure and a significant decrease in lactate dehydrogenase release. AVE did not affect PTP opening directly in isolated mitochondria. CONCLUSION: The beneficial effect of NHE-1 inhibition in hearts subjected to IR is associated with attenuation of mitochondrial PTP opening and apoptosis and the resultant mitochondrial dysfunction. The effect of AVE on PTP opening most likely is indirect, as pore opening was not affected by direct administration of AVE to mitochondrial suspensions.     

Compensated volume overload increases the vulnerability of heart mitochondria without affecting their functions in the absence of stress

Although mitochondrial dysfunction has often been associated to heart failure, it has been suggested that it may represent only a late phenomenon in the disease process. We hypothesized that mitochondrial vulnerability to stress could be impaired in hypertrophied but non-decompensated hearts at a time when overt mitochondrial defects are not yet apparent. In the present study, hypertrophic remodeling was induced by means of an aorto-caval fistula (ACF) in WKHA rats and experiments were performed 12 weeks post surgery. At this time, ACF animals displayed normal contractile function, tissue oxidative capacity as well as mitochondrial membrane potential and respiratory function. However, compared to sham, mitochondria from ACF animals were more vulnerable to anoxia–reoxygenation injury in vitro as indicated by a greater impairment of oxidative phosphorylation and a greater dependence of respiration on exogenous NADH. Addition of the PTP inhibitor CsA restored respiratory function to the level observed in mitochondria from sham animals. Likewise, mitochondria from ACF displayed a greater sensitivity to Ca²⁺-induced PTP opening in vitro compared to their sham counterparts. In addition to the greater vulnerability of mitochondria in vitro, mitochondrial PTP opening measured in situ in perfused hearts was greater following ischemia–reperfusion in ACF animals than in their sham counterparts. This was associated with a more impaired functional recovery and greater tissue damage during reperfusion in hearts from ACF vs sham. Taken together, these results indicate that, in response to volume overload, mitochondria may display increased vulnerability in the absence of any sign of dysfunction under baseline unstressed conditions, at a time when adverse ventricular remodelling is observed but systolic dysfunction and decompensation have not occurred yet.     

The mitochondrial permeability transition pore: Molecular nature and role as a target in cardioprotection

The mitochondrial permeability transition (PT) – an abrupt increase permeability of the inner membrane to solutes – is a causative event in ischemia–reperfusion injury of the heart, and the focus of intense research in cardioprotection. The PT is due to opening of the PT pore (PTP), a high conductance channel that is critically regulated by a variety of pathophysiological effectors. Very recent work indicates that the PTP forms from the F-ATP synthase, which would switch from an energy-conserving to an energy-dissipating device. This review provides an update on the current debate on how this transition is achieved, and on the PTP as a target for therapeutic intervention. This article is part of a Special Issue entitled "Mitochondria: from basic mitochondrial biology to cardiovascular disease".     

Compensated volume overload increases the vulnerability of heart mitochondria without affecting their functions in the absence of stress

Although mitochondrial dysfunction has often been associated to heart failure, it has been suggested that it may represent only a late phenomenon in the disease process. We hypothesized that mitochondrial vulnerability to stress could be impaired in hypertrophied but non-decompensated hearts at a time when overt mitochondrial defects are not yet apparent. In the present study, hypertrophic remodeling was induced by means of an aorto-caval fistula (ACF) in WKHA rats and experiments were performed 12 weeks post surgery. At this time, ACF animals displayed normal contractile function, tissue oxidative capacity as well as mitochondrial membrane potential and respiratory function. However, compared to sham, mitochondria from ACF animals were more vulnerable to anoxia-reoxygenation injury in vitro as indicated by a greater impairment of oxidative phosphorylation and a greater dependence of respiration on exogenous NADH. Addition of the PTP inhibitor CsA restored respiratory function to the level observed in mitochondria from sham animals. Likewise, mitochondria from ACF displayed a greater sensitivity to Ca(2+)-induced PTP opening in vitro compared to their sham counterparts. In addition to the greater vulnerability of mitochondria in vitro, mitochondrial PTP opening measured in situ in perfused hearts was greater following ischemia-reperfusion in ACF animals than in their sham counterparts. This was associated with a more impaired functional recovery and greater tissue damage during reperfusion in hearts from ACF vs sham. Taken together, these results indicate that, in response to volume overload, mitochondria may display increased vulnerability in the absence of any sign of dysfunction under baseline unstressed conditions, at a time when adverse ventricular remodelling is observed but systolic dysfunction and decompensation have not occurred yet.     

Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition

Mitochondria have been suggested to be causally linked to age-related alterations through respiratory chain dysfunction and formation of reactive oxygen species, leading to damage of mitochondrial DNA. Impaired biosynthesis of respiratory chain and ATP synthase subunits encoded by mitochondrial genes would set up a vicious cycle contributing to the aging process. Mitochondria are also involved in the increased susceptibility to ischemic injury observed in aged hearts, a process where the mitochondrial permeability transition pore (PTP) may play a role. Here, we analyze (i) the possible mechanisms through which PTP opening might contribute to age-related myocardial alterations; (ii) the available evidence of an increased probability of PTP opening in mitochondria isolated from aged tissues; (iii) the current methodological limitations that complicate the elucidation of causal relationships between PTP opening, mitochondrial dysfunction, and myocardial aging.     

Increased expression and intramitochondrial translocation of cyclophilin-D associates with increased vulnerability of the permeability transition pore to stress-induced opening during compensated ventricular hypertrophy

Opening of the permeability transition pore (PTP) of mitochondria is a critical permeation event that compromises cell viability and may constitute a factor that participates to the loss of cardiomyocytes in compromised hearts. Mitochondria from hearts with volume overload-induced compensated hypertrophy are more vulnerable to opening of the PTP opening in response to a Ca²⁺ stress. Several of the factors known to affect PTP opening, including respiratory function, membrane potential, the rate of mitochondrial Ca²⁺ uptake and endogenous levels of Ca²⁺ in the mitochondrial matrix, were not altered by volume overload. In contrast, there was an 80% increase in the abundance of the PTP regulating protein cyclophilin-D and a 3.7 fold enhancement of Cyp-D binding to membrane, which all predispose to PTP opening. Mitochondria from volume overloaded animals also displayed elevated rates of production of reactive oxygen species, which may be causally related to both the intramitochondrial translocation of cyclophilin-D and PTP opening, since incubation of cardiac mitochondria with terbutylhydroperoxyde in vitro increased to binding of cyclophilin-D to mitochondrial membranes in a dose-related fashion, except when cyclosporin A (a ligand of cyclophilin D with a known ability to delay PTP opening) was present prior to the addition of terbutylhydroperoxyde. Taken together, these results constitute the first evidence obtained in a pathophysiologic situation that increased abundance of cyclophilin-D within mitochondrial membranes may increase mitochondrial vulnerability to stress, and thus possibly initiate a vicious cycle of cellular dysfunction that may ultimately lead to activation of cell death.     

Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia

Mitochondrial permeability transition (PT) is a phenomenon induced by high levels of matrix calcium and is characterized by the opening of the PT pore (PTP). Activation of the PTP results in loss of mitochondrial membrane potential, expansion of the matrix, and rupture of the mitochondrial outer membrane. Consequently, PT has been implicated in both apoptotic and necrotic cell death. Cyclophilin D (CypD) appears to be a critical component of the PTP. To investigate the role of CypD in cell death, we created a CypD-deficient mouse. In vitro, CypD-deficient mitochondria showed an increased capacity to retain calcium and were no longer susceptible to PT induced by the addition of calcium. CypD-deficient primary mouse embryonic fibroblasts (MEFs) were as susceptible to classical apoptotic stimuli as the WT, suggesting that CypD is not a central component of cell death in response to these specific death stimuli. However, CypD-deficient MEFs were significantly less susceptible than their WT counterparts to cell death induced by hydrogen peroxide, implicating CypD in oxidative stress-induced cell death. Importantly, CypD-deficient mice displayed a dramatic reduction in brain infarct size after acute middle cerebral artery occlusion and reperfusion, strongly supporting an essential role for CypD in an ischemic injury model in which calcium overload and oxidative stress have been implicated.     

The mitochondrial effects of novel apoptogenic molecules generated by psoralen photolysis as a crucial mechanism in PUVA therapy

The generation of photoproducts of psoralen (POPs) might be relevant in cell death induced by psoralen plus UVA, namely PUVA, which is a recognized effective treatment for cutaneous T-cell lymphoma, chronic graft-versus-host disease, and psoriasis. We investigated the occurrence of POP-induced cell death and the underlying mechanisms. POPs were produced by irradiating a psoralen solution with UVA. Jurkat cells treated in the dark with these mixtures died mainly through an apoptotic mechanism. POPs were separated by high-performance liquid chromatography (HPLC), and cells were added with each of these fractions. A total of 2 dimers of psoralen and 6-formyl-7-hydroxycoumarin (FHC) were identified in the apoptogenic fractions. Apoptosis was preceded by mitochondrial dysfunction caused by the opening of the mitochondrial permeability transition pore (PTP). In fact, both mitochondrial depolarization and cell death were prevented by the PTP inhibitor cyclosporin A (CsA). PTP opening was also documented in isolated mitochondria added with POP, suggesting that apoptosis is caused by a direct effect of POP on mitochondria. In fact, FHC alone induced PTP opening and CsA-inhibitable cell death of Jurkat cells, whereas nontransformed T lymphocytes were resistant. Along with identifying novel apoptogenic molecules, the present results indicate that POP generation directs transformed cells to apoptosis.     

A CaPful of mechanisms regulating the mitochondrial permeability transition

Despite the lack of its molecular identification, the mitochondrial permeability transition pore (PTP) is a fascinating subject because of its important role in cell death. This holds especially true for cardiovascular diseases and in particular for ischemia–reperfusion injury, where research on PTP inhibition has been successfully translated from bench to clinical evidence of cardioprotection. In addition, recent reports extend the relevance of PTP to heart failure and atherosclerosis. This review summarizes the major factors involved in PTP control with specific emphasis on cardiovascular pathophysiology, and highlights recent findings on the pivotal role of inorganic phosphate as a mediator of the inhibitory effects of cyclosporin A and cyclophilin D ablation.     

Melatonin prevents oxidative stress-mediated mitochondrial permeability transition and death in skeletal muscle cells

Abstract:  Oxidative stress-induced mitochondrial dysfunction plays a crucial role in the pathogenesis of a wide range of diseases including muscle disorders . In this study, we demonstrate that melatonin readily rescued mitochondria from oxidative stress-induced dysfunction and effectively prevented subsequent apoptosis of primary muscle cultures prepared from C57BL/6J mice. In particular, melatonin (10⁻⁴–10⁻⁶  m ) fully prevented myotube death induced by tert -butylhydroperoxide ( t -BHP; 10 μ m –24 hr) as assessed by acid phosphatase, caspase-3 activities and cellular morphological changes. Using fluorescence imaging, we showed that the mitochondrial protection provided by melatonin was associated with an inhibition of t -BHP-induced reactive oxygen species generation. In line with this observation, melatonin prevented t -BHP-induced mitochondrial depolarization and mitochondrial permeability transition pore (PTP) opening. This was associated with a highly reduced environment as reflected by an increased glutathione content and an increased ability to maintain mitochondrial pyridine nucleotides and glutathione in a reduced state. Using isolated mitochondria, in a similar manner as cyclosporin A, melatonin (10⁻⁸–10⁻⁶  m ) desensitized the PTP to Ca²⁺ and prevented t -BHP-induced mitochondrial swelling, pyridine nucleotide and glutathione oxidation. In conclusion, our findings suggest that inhibition of the PTP essentially contributes to the protective effect of melatonin against oxidative stress in myotubes.     

INTERMITTENT HYPOXIA CONDITIONING PREVENTS OXIDATIVE BRAIN INJURY IN ETHANOL WITHDRAWN RATS

Cyclic bouts of intermittent, normobaric hypoxia (IH) have been found to protect the central nervous system from ischemic and excitotoxic injury. We investigated whether IH mitigates oxidative brain injury in male rats subjected to ethanol intoxication and abrupt ethanol withdrawal (EW). We assessed the effects of IH on superoxide generation, protein oxidation, and mitochondrial membrane swelling and rupture as a marker of mitochondrial permeability transition pore (PTP) opening. Male rats consumed dextrin control diet or 6.5% ethanol diet for 5 weeks. During the last 20 days of the diet, rats were treated with repetitive (5-8/day), brief (5-10 min) periods of hypoxia (9.5-10% inspired O₂) separated by 4 min exposures to room air. Cerebellum, cortex and hippocampus were biopsied at the end of the ethanol diet or at 24 hours of EW. Superoxide and protein carbonyl contents in tissue homogenates and rate of absorbance decline at 540 nm in mitochondrial suspensions were measured as indicators of oxidative stress, protein oxidation and PTP opening, respectively. EW increased superoxide and protein carbonyl contents and accelerated PTP opening in all three brain areas in a manner that was ameliorated by IH. These results suggest that antecedent IH conditioning during chronic ethanol consumption attenuates subsequent oxidative damage to the brain in ethanol withdrawn rats. (supported by NIAAA/AA013864, NIAAA/AA015982, NCCAM/AT003598).     

环孢素A在心肌缺血再灌注损伤中的心脏保护作用研究进展

越来越多的证据显示线粒体通透性转换孔（mPTP）的开放在心肌缺血再灌注损伤中发挥着关键作用。尽管其结构仍不明确,但亲环素D却是其主要的组成成分之一。环孢素A是一种有效的免疫抑制剂,可结合于线粒体亲环素D,从而抑制mPTP的开放。许多动物实验及部分小规模临床研究表明,其可以通过抑制mPTP而减少心肌梗死面积。然而,也有研究提示环孢素A并没有心脏保护作用。现就环孢素A在心肌缺血再灌注损伤中可能的心脏保护作用机制、相关的动物实验模型及临床研究、可能的影响因素及进一步研究方向进行综述。     

Mitochondrial permeability transition pore and postconditioning

Postconditioning has recently been described as a powerful cardioprotection that prevents lethal reperfusion injury. Growing evidence suggests that mitochondrial permeability transition may be a key event in postconditioning. This proposition arises from the complementary observations that: (1) conditions for the mitochondrial permeability transition pore (mPTP) opening are built up during early reperfusion, (2) mPTP opens at the time of reperfusion, (3) transgenic structural alteration of mPTP modifies its opening probability following ischemia-reperfusion, (4) mPTP plays a role in preconditioning, and (5) postconditioning attenuates lethal reperfusion injury. We review in this article current evidence for an important role of the mitochondrial transition pore in postconditioning.     

Role of energy metabolism in the preconditioned heart--a possible contribution of mitochondria.

A brief period of ischemia and reperfusion has been shown to protect the myocardium against subsequent sustained ischemia and reperfusion injury, which is called "preconditioning". A great number of investigators have explored the mechanisms underlying this preconditioning-induced cardioprotection. This article dealt with possible mechanisms of energy metabolism and mitochondrial activity for preconditioning-induced cardioprotection. Particularly, the contribution of energy metabolites produced during a brief period of ischemia and reperfusion injury, as well as mitochondrial function that is modified by changes in mitochondrial ATPase activity, opening of mitochondrial ATP-dependent potassium channels and production of free radicals in mitochondria, to ischemic preconditioning is discussed.     

线粒体融合蛋白2在心血管疾病中的研究现状

线粒体是一个处于不断地融合与分裂过程中的动态细胞器。线粒体融合蛋白2(Mfn2)作为广泛分布于线粒体外膜和线粒体结合内质网膜上具有多重功能的蛋白,参与维持正常细胞功能。除了参与线粒体融合外,Mfn2还能够调节线粒体代谢、促进损伤线粒体的自噬、增强线粒体与内质网交流、维持内质网功能及通过调控线粒体外膜通透性和渗透性钙转运孔道的启闭参与细胞死亡过程等。另外,Mfn2基因还可通过调控Ras-Raf-ERK/MAPK和Ras-PI3K-Akt信号通路分别参与调控血管平滑肌细胞的增殖和凋亡过程。Mfn2的这一系列重要的生物学功能有助于其参与高血压、肺动脉高压、动脉粥样硬化、急性缺血/再灌损伤、扩张性心肌病、心肌肥大、心衰和肥胖糖尿病等多种心血管疾病的发生发展过程。研究Mfn2与心血管疾病的相关性也许能为临床提供一个心血管疾病潜在治疗的靶点。因此,本文将综述Mfn2在心血管疾病相关研究中的现状。