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Cardiovascular disease (CVD) is a group of systemic disorders threatening human health with complex pathogenesis, among which mitochondrial energy metabolism reprogramming has a critical role. Mitochondria are cell organelles that fuel the energy essential for biochemical reactions and maintain normal physiological functions of the body. Mitochondrial metabolic disorders are extensively involved in the progression of CVD, especially for energy-demanding organs such as the heart. Therefore, elucidating the role of mitochondrial metabolism in the progression of CVD is of great significance to further understand the pathogenesis of CVD and explore preventive and therapeutic methods.
- cardiovascular disease
- mitochondrial metabolism
- mitochondrial calcium
1. Introduction
Cardiovascular disease (CVD) remains the leading cause of death and disease burden worldwide [1]. Energy-demanding organs such as the heart are affected by mitochondrial function, and the relationship between mitochondrial metabolism and CVD has been widely proved [2,3,4,5,6,7]. Mitochondrial metabolism is a highly complex energy-releasing process involving a series of enzymatic reactions, during which sugars, fats, and proteins are oxidized through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS). Mitochondrial dysfunction is a symbol of the exacerbated intracellular environment leading to diseases such as CVD [2,3,4,5,6,7]. Regulating mitochondrial metabolism is a promising therapeutic strategy for CVD.
2. Mitochondrial Metabolism Dysfunction in CVD
Mitochondrial metabolism is the main source of energy supply for most cells, especially for energy-consuming cells, such as cardiomyocytes. The glucose OXPHOS in the mitochondria is the major metabolism pathway in most cells. OXPHOS is, indeed, a more efficient means of generating ATP than glycolysis [8]. Mitochondrial metabolic dysfunction has been widely reported in CVD, characterized by metabolic reprogramming [9]. In pulmonary arterial hypertension (PAH), a significant metabolic reprogramming is observed, that is, in pulmonary artery smooth muscle cells (PASMCs), the level of OXPHOS is significantly reduced, and the levels of glycolysis and fatty acid oxidation (FAO) are significantly increased [10,11]. Similar metabolic reprogramming from glucose OXPHOS to glycolysis occurs in aortic smooth muscle cells (SMCs) in the development of aneurysms and atherosclerotic diseases [5,12]. The major metabolism pathway in cardiomyocytes is FAO. During the progression of heart failure, metabolism shifts from majorly relying on FAO to OXPHOS in the early stage then leans to glycolysis in the late stage [13].
3. Major Factors in Mitochondrial Metabolism
3.1. Mitochondrial DNA
Mitochondria are the only semi-autonomous genetic organelles in mammalian cells with their own transcriptional and translational system independent of the nucleus. Mitochondria autonomously synthesize a variety of key proteins and enzymes by mitochondrial DNA (mtDNA). mtDNA is mainly distributed in the mitochondrial matrix and inner membrane and contains a double-stranded circular DNA with a molecular weight of 16.5 kb, 16,569 nucleotide pairs, coding sequences of 37 genes, 2 ribosomal RNAs, 22 transporter RNAs, and 13 genes encoding important component proteins that are closely related to mitochondrial OXPHOS [14,15]. mtDNA plays an extremely important role in providing the template for translating enzymes that maintain the normal mitochondrial OXPHOS process and cell function. The enzyme includes 7 mitochondrial oxidative respiratory chain NADH dehydrogenase subunits, 1 cytochrome B, 3 cytochrome C oxidase subunits, and 2 ATP synthetases [16]. Due to the absence of introns and histones in mtDNA, and the lack of a similar DNA repair system in the nucleus, mtDNA is more susceptible to oxidative damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS) [17].
3.2. Mitochondrial Dynamics
Mitochondrial dynamics refers to the dynamic cycle of biogenesis, fusion, fission, and degradation that mitochondria continuously undergo to maintain their integrity, distribution, and morphology [26]. These processes reflect the early adaptation of mitochondria in response to external stimuli, maintaining overall mitochondrial function by removing irreversibly damaged parts and preserving the functional parts. In different tissues and cells, mitochondria morphology and network structure vary. In cardiomyocytes, mitochondria are numerous, covered with ridges, and spherical in shape, while in lymphocytes, the mitochondria are few in the count, tube-shaped. This also shows that the correlation of different morphological features of mitochondria with the energy requirements of tissue cells. Increasing evidences show that the disturbance of mitochondrial dynamics is extensively involved in the progression of CVD, including heart failure [27,28], myocardial ischemia/reperfusion (I/R) injury [29], abdominal aortic aneurysm (AAA) [30] and PAH [31,32].
3.2.1. Mitochondrial Fusion
Mitochondrial fusion is an important process that enables the exchange of DNA, proteins, lipids, and metabolites between different mitochondria [33]. Mitochondrial fusion consists of two processes, outer and inner membrane fusion, regulated by the nuclear-encoded dynamin-related GTPases protein family membrane fusion proteins 1 (Mfn1), membrane fusion proteins 2 (Mfn2), and optic atrophy protein 1 (OPA1). The outer membrane fusion is dependent on Mfn1 and Mfn2, while OPA1, located in the inner mitochondrial membrane, is involved in the inner mitochondrial membrane fusion. Numerous studies have shown that mitochondrial fusion is involved in mitochondrial metabolism [34]. Mfn2 can interact with pyruvate kinase isozyme type M2 (PKM2) to promote mitochondrial fusion, facilitate OXPHOS, and inhibit glycolysis [35]. In both yeast and mammalian cells, blocking mitochondrial fusion can lead to mitochondrial dysfunction and inadequate ATP supply [36]. Loss-of-function mutations of Mfn1 and Mfn2 cause: (1) decreased cellular glucose oxidation level, (2) depolarization of the mitochondrial membrane potential, (3) inhibition of the mitochondrial TCA and oxidative respiration, (4) conversion of cellular energy metabolism from OXPHOS to glycolysis, and (5) severe cellular functional defects. Whereas stress-induced mitochondrial fusion restores mitochondrial ATP production [37]. When mitochondrial OXPHOS is blocked, it causes an increase in mitochondrial ROS (mtROS), which triggers oxidative damage to mitochondria and increases mtDNA mutations.
3.2.2. Mitochondrial Fission
Mitochondrial fission is mainly mediated by mitochondrial fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1) in the cytoplasm. Under physiological conditions, mitochondrial division can serve the purpose of isolating irreversibly damaged DNA or toxic material from the mitochondria, and defective mitochondria are removed via the mitophagy pathway when the mitochondrial membrane potential and pH gradient fail to meet the requirements for fusion. Thus, moderate mitochondrial division is beneficial to maintain normal cellular energy metabolism. However, excessive mitochondrial fission inhibits the respiratory chain, represses ATP production, and leads to cellular dysfunction [41,42].
There is an imbalance in [Ca2+]m homeostasis is an important cause of CVD [55]. For example, heart-specific knockdown of VDAC2 has been found to cause [Ca2+]m imbalance and dilated cardiomyopathy [56]. Similarly, a lack of MCU has been found to promote PASMC proliferation and apoptosis resistance in human and experimental PAH models, and restoring MCU expression can alleviate the symptoms of experimental PAH [57]. Therefore, the maintenance of [Ca2+]m homeostasis is essential to maintaining the normal energy metabolism of mitochondria and the function of the body. [Ca2+]m imbalance can be caused by [Ca2+]m overload. Numerous studies have shown that when [Ca2+]m is abnormally increased, may cause [Ca2+]m overload, resulting in oxidative stress, mitochondrial structural damage, and dysfunction of mitochondria, which in turn reduces ATP production and triggers cell apoptosis [2,58,59,60,61]. Nevertheless, [Ca2+]m itself is a key factor in regulating mitochondrial ATP production by participating in the following processes. Ca2+ can activate pyruvate dehydrogenase complex (PDC), a complex enzyme composed of multiple subunits [62], isocitrate dehydrogenase (IDH), a key TCA rate-limiting enzyme [63], and 2-oxoglutarate dehydrogenase complex (OGDC) in the mitochondrial matrix [64,65,66]. When glucose is converted to pyruvate in the cytosol, it is transported to the mitochondria and catalyzed by PDC to acetyl coenzyme A (acetyl-CoA). Acetyl-CoA undergoes the TCA producing carbon dioxide, GTP, and NADH. Ca2+ can enhance PDC activity by binding to pyruvate dehydrogenase (PDH) phosphatase subunit 1 (PDP1), which accelerates the conversion of pyruvate to acetyl-CoA [67,68] and promote the ATP production through dephosphorylation of the PDH subunit [69]. Meanwhile, Ca2+ can accelerate the TCA by enhancing the activity of IDH [70] and OGDC [71].
3.4. ROS
ROS refer to a class of free radicals composed of oxygen molecules with an odd number of electrons, characterized by a short half-life and high activity. Mitochondria are the main source of ROS when electrons leak during transfer and are captured by oxygen molecules. During OXPHOS, mitochondria transfer electrons from electron donors to electron acceptors through the electron transfer chain, catalyze the generation of ATP and reduce oxygen molecules to water. Some studies have speculated that about 0.2–2% of these consumed oxygen molecules are converted to ROS [79]. In physiological conditions, low levels of ROS can act as signaling molecules that participate in mitochondrial metabolism [80,81,82,83,84], and promote adaptive upregulation of antioxidant enzymes to maintain the body’s health [85]. ROS could be rapidly scavenged by antioxidant enzymes, such as superoxide dismutase 2 (SOD2), glutathione reductase, and catalase. When ROS exceed the clearance capacity of the antioxidant system, excessive ROS may damage proteins, lipids, and mtDNA in mitochondria causing oxidative stress and diseases [86], such as CVD [87]. Therefore, to avoid cellular dysfunction, redox homeostasis must be strictly controlled in case of excessive ROS accumulation [88].
4. Mitochondrial Metabolism Disorder and CVD
4.1. PAH
PAH is a heterogeneous and fatal disease of the pulmonary vasculature, clinically defined as resting mean pulmonary artery pressure >20 mmHg, and normal left atrial pressure and pulmonary vascular resistance ≥3 Wood units [97]. PAH is characterized by occlusive remodeling and increased resistance caused by persistent pulmonary vasoconstriction, leading to right ventricular hypertrophy and heart failure. Excessive proliferation and apoptosis resistance of PASMCs and pulmonary artery endothelial cells (PAECs) are the main causes of pulmonary vascular remodeling.
The association of metabolic reprogramming and PAH has become a consensus over the past decades [98]. In PAH, a shift of energy metabolism from OXPHOS of glucose to cytoplasmic glycolysis in PASMCs and PAECs has been widely demonstrated in human lung-derived cell cultures and multiple mouse models of PAH, and the prevailing view is that the driving force for this metabolic shift stems from the pathological accumulation of hypoxia-inducible factor 1α (HIF-1α) [99]. HIF-1α is a hypoxia-inducible protein that significantly promotes glycolytic metabolism and is a core regulator of the body’s adaptive repair of the intracellular oxygen environment, playing an important role in a variety of physiological functions including cell proliferation, pro-survival, angiogenesis and metabolism. In the development of PAH, HIF-1α accumulation is accompanied by an increase in glycolysis and glycolysis-related enzyme activities [10]. In contrast, mitochondrial glucose OXPHOS decreases significantly in the pulmonary artery. However, it is noteworthy that the levels of enzymes related to fatty acid metabolism and FAO in mitochondria of PASMCs and PAECs are significantly increased in a variety of PAH models [100,101,102].
4.2. Aortic Aneurysm
Aortic aneurysm is an aortic dilatation disease caused by multiple factors, characterized by irreversible dilatation of the aortic diameter beyond 50% of the normal diameter or the abdominal aortic diameter ≥3 cm. Risk factors for aneurysms include smoking, age, and genetics. When an aortic aneurysm occurs, the risk of aneurysm rupture gradually increases parallel with the continued expansion of the aorta and the enlargement of the aneurysm. Once the aneurysm ruptures, the chance of fatality will be greater than 80% [112]. Moreover, due to the insidious nature of aneurysm development, patients may not show any clinical symptoms before the aneurysm rupture. Therefore, aneurysm rupture is the greatest risk factor for death in patients with an aneurysm. Because of the lack of a specific drug and the short time from onset to death, early screening is an important clinical precaution method, for aneurysms larger than 5.5 cm in diameter, the main treatment is endovascular aortic repair and surgery. It is urgent to determine the pathogenesis of aneurysms and develop targeted drugs. The main features of aneurysms are excessive proliferation and migration of aortic SMCs, increased secretion of extracellular matrix and degradation of elastic fiber, which cause vascular remodeling. Inflammation and redox imbalance are considered important drivers of aneurysm development. Chronic vascular inflammation can recruit immune cells, amplify the inflammatory response, cause SMCs dysfunction and apoptosis, and eventually lead to aortic smooth muscle tissue damage, causing an aneurysm [113].
4.3. Atherosclerosis
Atherosclerosis, a vascular disease characterized by lipid deposition and inflammation in the arterial wall, is the pathological cause of coronary heart disease and peripheral vascular diseases imposing a serious risk to health. Vascular endothelial cells (ECs), macrophages, and SMCs are the main cell types chronologically involved in the development of atherosclerosis. As initiates with hypercholesterolemia-induced endothelial dysfunction [118], damaged ECs trigger inflammation to recruit monocytes. Monocytes are induced to M1 macrophages, which accelerate the local inflammatory reaction and promote abnormal proliferation of SMCs leading to formation of atherosclerosis.
Glycolysis is the main form of energy metabolism in ECs and M1 macrophages [120,121]. Studies have found that the expression of glycolysis-related enzymes and glycolysis in ECs are significantly down-regulated in atherosclerosis [122]. In contrast, in atherosclerosis, inflammatory factors can promote the metabolic reprogramming of M1 macrophages from myelocytomatosis viral oncogene-dependent to HIF-1α-dependent, which enhances glycolysis [123]. While under hypoxia, either knockdown of HIF-1α or inhibition of the expression of glycolytic related protein 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) can significantly hamper the glycolysis in macrophages, reduce the expression of tumor necrosis factor-alpha (TNF-α), and promote macrophage apoptosis [124].
4.4. Heart Failure
Cardiomyocytes contains large numbers of mitochondria as heart is one of the most energy-consuming organs of the body. Thus, disturbances in mitochondrial metabolism can lead to an inadequate energy supply to the heart and cause cardiac dysfunction. The reprogramming of cardiac energy metabolism during the development of heart failure has been widely demonstrated [13,127,128]. Under physiological conditions, about 40–60% of the energy required for myocardial activity derives from mitochondrial FAO, and the rest mainly comes from the oxidation of sugars, ketones and amino acids [129].
5. Mitochondria-Targeted Therapeutic Agents and Strategies in CVD
Current strategies for mitochondrially targeted therapy mainly focus on factors of mitochondrial damage, such as decreased ATP/ADP ratio, signal pathway changes caused by insufficient NAD+, ROS-induced metabolic disorders, and [Ca2+]m disorders caused by abnormal calcium channels which lead to strategies for mitochondria-targeted drug delivery: (1) cationic carriers designed using mitochondrial membrane potential coupled with drugs, such as mitoquinone (MitoQ) coupled with lipophilic triphenylphosphonium (TPP+), (2) mitochondrially targeted signal peptides as carriers for drug delivery, such as Szeto-Schiller peptide 31 (SS-31), (3) liposomes as carriers, such as mitochondria-targeted dendritic lipopeptide liposomal delivery platform [137], (4) nanoparticles coated with drugs for delivery, such as mitochondria-targeted nanoparticles (CsA@PLGA-PEG-SS31) [138], (5) physical invasion methods, such as microinjection of mitochondria directly into cells [139], (6) gene therapy technology, such as mitoTALENs technology [140].
5.1. Potential Mitochondrial Targets for CVD
5.1.1. MPTP
MPTP, a complex assembled by a group of proteins, is a non-specific channel located between the inner and outer membranes of mitochondria. Numerous studies have shown that MPTP plays important roles in mitochondria-induced apoptosis [142,143]. Under stress conditions, mitochondrial oxidative stress can lead to [Ca2+]m overload by increasing [Ca2+]m uptake, causing the opening of MPTP, which in turn leads to a decrease in mitochondrial membrane potential and release of cytochrome C, triggering of mitochondrial apoptosis signal to induce cell apoptosis [144,145].
5.1.2. Sirtuin 3 (Sirt3)
Acetylation of mitochondrial proteins is involved in the pathogenesis of CVD [152]. Sirt3 is a member of the histone deacetylase sirtuin family localized in mitochondria. Proteomic analysis reveals that most of the mitochondrial proteins can be modified by acetylation, and Sirt3 plays an important role in the deacetylation of these proteins [153].
5.1.3. [Ca2+]m
[Ca2+]m homeostasis is vital for mitochondrial metabolism and CVD [56,57]. In recent years, methods of restoring [Ca2+]m imbalance, namely modulating mitochondrial calcium uptakes/release channels such as VDACs, MCU or NLX, have attracted a lot of attentions. It is considered that [Ca2+]m overload caused by MCU complex activation is the underlying mechanism of cardiac I/R injury.
5.1.4. Mitochondrial Dynamics
Mitochondrial dynamics is mainly characterized by a dynamic balance between mitochondrial fission and fusion. Mitochondrial fission and fusion have an important role in the mitochondrial material exchange, repair, and removal of damaged mitochondria, and are an important means for the body to maintain mitochondrial health. Extreme states of excessive fission or fusion are detrimental to health [160]. Under physiological or pathological conditions, mitochondrial fission and fusion form new homeostasis to meet the energy or physiological needs of the cell.
5.2. Mitochondria-Targeted Agents for CVD
5.2.1. CoQ10 and MitoQ
CoQ10 is one of the electron carriers in the mitochondrial ETC. It is involved in mediating the electron transfer between mitochondrial OXPHOS complex I/II and complex III and plays an important role in maintaining mitochondrial aerobic respiration and ATP production. CoQ10 is widely used in the treatment of metabolism-related diseases because of its powerful antioxidant protective effect, which protects mitochondria from oxidative damage to maintain normal mitochondrial metabolic function. Due to the double membrane structure of mitochondria, CoQ10 cannot effectively enter mitochondria, resulting in low bioavailability. Scientists synthesize MitoQ with mitochondria-targeted function by covalently coupling the benzoquinone part of CoQ10 and TPP+ through the deca-carbon aliphatic chain by taking advantage of the mitochondrial membrane potential targeting property of TPP+. MitoQ has been widely used in the treatment of various metabolic syndromes [165].
5.2.2. Melatonin
Melatonin is a neuroendocrine hormone produced by the pineal gland of mammals and its physiological functions include neuroregulation, sleep promotion, antioxidant, anti-inflammation, anti-aging, immune regulation, endocrine regulation and cell growth promotion [174]. The level of melatonin varies greatly among different populations and decreases gradually with aging. Melatonin has amphipathic properties enabling itself penetrating through a variety of cell membranes. Melatonin can quickly cross the cellular and mitochondrial membranes and accumulate in mitochondria [175]. Due to its powerful antioxidant and anti-inflammatory properties, melatonin has been widely used in therapeutic studies of CVD. Encouragingly, most studies have found a protective effect of melatonin in heart failure [176], cardiac I/R injury [177], aneurysm [178,179], atherosclerosis [180], and PAH [181,182].
5.2.3. SS-31
SS-31 is widely used in CVD treatment. In the aging heart, SS-31 reduces oxidative stress and mitochondrial electron leakage, inhibits the opening of MPTP, improves cardiac energy metabolism, restores mitochondrial activity, promotes ATP generation, and alleviates cardiac diastolic function [203,204,205]. Cardiac proteomics studies have found that SS-31 ameliorates aging-induced changes in the post-translational modification profile of cardiac proteins [206,207], improves transverse aortic constriction (TAC)-induced mitochondrial damage and heart failure phenotypes, and suppresses mitochondrial proteomic changes [208]. Preclinical studies have shown that SS-31 by its anti-inflammatory and anti-oxidant effects alleviates sepsis-induced cardiac injury [209], improves failing heart function, ameliorates myocardial mitochondrial fragmentation [210], maintains myocardial mitochondrial integrity, and improves myocardial energy supply in rats with I/R [211,212]. In addition, SS-31 can also remove ROS, stabilize mitochondrial membrane potential, reduce cardiomyocyte apoptosis, and alleviate diastolic cardiomyopathy and myocardial toxicity induced by doxorubicin in rats [213,214]. In high-fat diet ApoE knockout mice, administration of SS-31 inhibits cholesterol uptake, which in turn inhibits foam cell formation and atherosclerosis progression [215]. In TAC-induced PAH mice model, SS-31 can inhibit the release of inflammatory factors and improve endothelial function by reducing the expression of pro-oxidant protein NOX1/NOX2, and reduce TAC-induced right ventricular systolic pressure [216]. These results indicate that SS-31 has great potential in the treatment of CVD.
5.2.4. MitoTEMPOL
MitoTEMPOL is a novel mitochondria-targeted antioxidant formed by the combination of the superoxide dismutase mimics Tempol and TPP+. MitoTEMPOL can scavenge mtROS, so it can alleviate the oxidative damage of mitochondria induced by mtROS under various pathological conditions, restore mitochondrial function, and maintain normal function of the body.
In CVD, MitoTEMPOL could improve ventricular arrhythmias, eliminate sudden cardiac death, and inhibit the expression of proteome remodeling and specific phosphoproteome alterations induced by chronic heart failure in guinea pigs, or preventing and reversing heart failure by removing ROS in the heart. Mechanistically, MitoTEMPOL repairs the disruption of normal coupling between cytoplasmic signaling and nuclear genetic programs, and restores the mitochondrial function, antioxidant enzymes, Ca2+ handling, and action potential repolarization disrupted by mtROS [221]. By clearing mtROS, MitoTEMPOL can inhibit the opening of the MPTP in the rat heart induced by nicotine, inhibit cardiac hypertrophy and cardiac fibrosis, and improve the sensitivity of rat myocardium to I/R injury caused by nicotine [222,223].
5.2.5. MitoSNO
Nitrosylation is one of the common post-translational modifications of proteins, which can regulate enzyme activity, subcellular localization and protein interactions. Studies have shown that nitrosylation modifications are also widely present in mitochondrial proteins and participate in the regulation of mitochondrial metabolic enzyme activities [227]. The reversible S-nitrosation modification is the main way that nitric oxide (NO) metabolism regulates mitochondrial physiology and pathology [227,228]. To further investigate the role of mitochondrial S-nitrosation, mitochondria-targeted MitoSNO has been formed by combining the NO donor SNAPNO (S-nitroso-N-acetylpenicillamine) and lipophilic TPP+. Driven by the positive charge of TPP+ and the mitochondrial inner membrane potential, MitoSNO accumulates rapidly in the mitochondria. Further study finds 13 S-nitrosation mitochondrial proteins, including aconitase, mitochondrial dehydrogenase and α-ketoglutarate dehydrogenase, whose activities are selectively and reversibly inhibited by S-nitrosation, indicating that S-nitrosation is reversibly involved in the regulation of enzyme activity of mitochondrial core metabolic enzymes [229].
5.3. Mitochondria-Targeted Gene Therapy Strategies
5.3.1. Mitochondria-Targeted Gene Editing Technologies
Because of the heterogeneity of mtDNA, mtDNA mutations need to accumulate to a threshold before they cause mitochondria-related diseases. For example, proband’s fibroblasts pathogenic variant m.8993T > G variant in MT-ATP6 subunit is 83%, and exhibits severe defects in mitochondrial cristae structure and decreased spare respiratory capacity in response to energy stress [234]. Therefore, it is a good idea to repair or excise mutated mtDNA by gene-editing technology to reduce the proportion of mutated mtDNA in the overall mtDNA. By combining an adeno-associated virus (AAV) 9-loaded TALEN (mitochondria-targeted TALEN, MitoTALEN) gene-editing tool with a mitochondrial guiding sequence, the m.5024C > T mutation site is successfully targeted to be cleaved, thus achieves the purpose of inhibiting the replication of the mutant gene. Six months after injection of this gene editing tool into the m.5024C > T mutant mouse model, the mtDNA mutation rate in mouse skeletal and heart muscle tissue decreases by 50%, most of the mutant genes are eliminated, and the mutation-induced reduction in transfer RNAAla levels is ameliorated [235].
5.3.2. Ectopic Expression of Mitochondrial Proteins
Ectopic expression of mitochondrial proteins is the process of constructing recombinant plasmids by combining mtDNA sequences encoding mitochondrial proteins and mitochondria-targeted sequences and integrating them into genomes through vectors (usually AAV) so that proteins originally expressed in mitochondria are sent to mitochondria through mitochondria-targeted peptides after being expressed in the nucleus and cytoplasm of cells to ameliorate metabolism dysfunction caused by impaired mitochondrial self-expression. Giovanni Manfredi et al. use ectopic expression of wild-type mtDNA encoding ATPase 6 of respiratory chain complex V in the nucleus and successfully import them into mitochondria, which significantly improve OXPHOS and ATP production in cells containing the ATP6 DNA 8993T > G mutation [240]. This technique allows the personalized design of recombinant plasmids to repair mitochondrial metabolic dysfunction caused by defects in mtDNA and is a potential mitochondria-targeted gene therapy strategy.
5.3.3. Mitochondrial Replacement Therapy (MRT) Technologies
The limitations of the conventional gene therapy approach make them fall short of expectations in the treatment of pathogenic mtDNA-defected diseases. MRT is the most effective technique for the prevention of hereditary mtDNA mutation disorders. This technique has been successfully tested in rhesus macaque monkeys [241] by transferring the nuclear genome of a mother carrying a pathogenic mtDNA mutation into the enucleated oocytes of another healthy mother by microinjection. However, the “three-parent” concept raised by this technique is controversial in terms of reproductive ethics. In addition, due to the possibility of selective replication and genetic drift, small amounts of residual maternally defective mtDNA may still gradually reach to pathogenic levels. Therefore, XiaoYan Fan et al. inject transmembrane peptide mRNA fused with autophagy receptor during nuclear transfer to reduce the carrying of defective mtDNA in reconstructed embryos by forcibly inducing the degradation of donor mitochondria [242]. To avoid ethical problems, scientists have developed co-culture technology to allow mtDNA-deficient cells to obtain autologous healthy mitochondria [243], or cytosolic fusion technology to fuse normal cells with mtDNA-deficient cells to form healthy hybrid cells to compensate for mitochondrial dysfunction in mtDNA-deficient cells [244].
This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14122760
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