**3.2. Mitochondria and ischemia/reperfusion (I/R)**

The normal function of the mitochondria maintains the endurance of the cardiomyocyte in the events of stress and increased workload. However, as soon as the series of biochemical alterations and damage in the mitochondria occur, the cell viability declines and regresses to cell death. Mitochondrial dysfunction contributes to cell damage during I/R. Myocardial ischemia is the result of the narrowing or blockage of the coronary artery, thereby depriving the cardiomyocytes from oxygen leading to hypoxia and damage to the heart region and disabling the heart to efficiently pump. The effects of hypoxia induce sudden biochemical and metabolic changes in the cardiomyocytes. These alterations induce mitochondrial membrane depolarization, reduction of ATP synthesis, and damage to the contractile function. With the cardiomyocytes being devoid of O2 , the cell metabolism changes to anaerobic respiration, inducing lactate accumulation and pH reduction. The increase in proton drives the Na+ -H+ ion exchanger to expel H+ from the cell in exchange for entry of Na+ ions [103]. Furthermore, due to the lack of ATP, 3Na+ -2 K+ ATPase fail to function causing more accumulation of Na+ and inducing the reverse function of the NCX pump to extrude Na+ and accumulate Ca2+ ions, promoting Ca2+ overload [104]. However, with prolonged ischemia, the increase in mitochondrial Ca2+, ROS, and decline of ATP level, the mPTP is triggered to be opened. These changes further result in mPTP opening, mediating both the necrotic and apoptotic cell death.

Although reperfusion restores the region of ischemia with new influx of O<sup>2</sup> , and the necessary substrates for aerobic ATP synthesis are delivered and extracellular pH has been restored, reperfusion has been proven to deliver damage at the same time. As blood flow reintroduces molecular oxygen to the damaged areas, ROS is generated. While the mitochondria generate ROS in normal physiology, the reperfusion of the ischemic region induces bursts of ROS production that overwhelms the ability of the cells to normally scavenge the reactive species [105]. It has been reported that upon reperfusion, while O2 supply is suddenly restored, the rapid normalization of the pH and the existing Ca2+ overload and oxidative stress triggers the mPTP to be opened [106, 107]. If the duration of the ischemia is relatively short, the biochemical changes would not be as severe, mPTP remains closed, and the cell will recover [58]. The activation of mPTP occurs in two stages [107]. In the first stage, during ischemia, due to the accumulation of fatty acids, loss of cytochrome c and antioxidants, the dissipation of the electrical potential across the membrane establishes the 'priming' formation of the mPTP. When reperfusion is introduced, the opening of the mPTP is triggered by multiple factors such as Ca2+ overload, increased free phosphate, ROS, and acidosis [107]. In addition, as the mitochondrial membrane potential continues to decline, mitochondrial and cytosolic Ca2+ levels continue to increase, leading to cell necrosis and apoptosis.

#### **3.3. Mitochondria and pressure overload–induced cardiac remodeling**

isoforms of NADP oxidase (Nox). Nox 4 is abundant in cardiomyocytes and is localized primarily in the mitochondria. Nox 4 has been reported to enhance ROS production in aging and in pressure overload–HF models [98–100] and also is highly active in failing human hearts [101]. Moreover, ROS plays a part in regulating cardiac hypertrophic pathways: Ras, protein

In summary, HF is characterized by bioenergetic imbalance between the energy production from mitochondria and demands from the myocardial performance. There are many complex simultaneous interplays between: the maintenance of ratio of CP/ATP, the level of total CK as a catalyst, the cycling of Ca2+ between the cytosol and the mitochondrial matrix, the major regulatory role of PGC-1α for mitochondrial biogenesis, FAO and glucose metabolism, and even the volume of cardiomyocyte in affecting mitochondria positioning that influences effi-

The normal function of the mitochondria maintains the endurance of the cardiomyocyte in the events of stress and increased workload. However, as soon as the series of biochemical alterations and damage in the mitochondria occur, the cell viability declines and regresses to cell death. Mitochondrial dysfunction contributes to cell damage during I/R. Myocardial ischemia is the result of the narrowing or blockage of the coronary artery, thereby depriving the cardiomyocytes from oxygen leading to hypoxia and damage to the heart region and disabling the heart to efficiently pump. The effects of hypoxia induce sudden biochemical and metabolic changes in the cardiomyocytes. These alterations induce mitochondrial membrane depolarization, reduction of ATP synthesis, and damage to the contractile function. With the

inducing lactate accumulation and pH reduction. The increase in proton drives the Na+


[105]. It has been reported that upon reperfusion, while O2

and inducing the reverse function of the NCX pump to extrude Na+

Although reperfusion restores the region of ischemia with new influx of O<sup>2</sup>

from the cell in exchange for entry of Na+

promoting Ca2+ overload [104]. However, with prolonged ischemia, the increase in mitochondrial Ca2+, ROS, and decline of ATP level, the mPTP is triggered to be opened. These changes

substrates for aerobic ATP synthesis are delivered and extracellular pH has been restored, reperfusion has been proven to deliver damage at the same time. As blood flow reintroduces molecular oxygen to the damaged areas, ROS is generated. While the mitochondria generate ROS in normal physiology, the reperfusion of the ischemic region induces bursts of ROS production that overwhelms the ability of the cells to normally scavenge the reactive species

rapid normalization of the pH and the existing Ca2+ overload and oxidative stress triggers the mPTP to be opened [106, 107]. If the duration of the ischemia is relatively short, the biochemical changes would not be as severe, mPTP remains closed, and the cell will recover [58]. The activation of mPTP occurs in two stages [107]. In the first stage, during ischemia, due to the accumulation of fatty acids, loss of cytochrome c and antioxidants, the dissipation of the electrical potential across the membrane establishes the 'priming' formation of the mPTP. When

further result in mPTP opening, mediating both the necrotic and apoptotic cell death.

, the cell metabolism changes to anaerobic respiration,

ATPase fail to function causing more accumulation of Na+


ions [103]. Furthermore,

and accumulate Ca2+ ions,

supply is suddenly restored, the

, and the necessary

kinase C, Jun N-terminal kinase, and mitogen-activated protein kinase [94, 102].

ciency of ATP production in cardiac mitochondria.

**3.2. Mitochondria and ischemia/reperfusion (I/R)**

cardiomyocytes being devoid of O2

ion exchanger to expel H+

42 Mitochondrial Diseases

due to the lack of ATP, 3Na+

Under physiological or pathological cardiac workload, the heart adapts through structural remodeling to meet the requirements. Remodeling at the cellular level induces alterations in organelle structure, intercellular protein, and gene expression [108]. At the early stages of cardiac hypertrophy, there are enhancement and preservation of the mitochondrial oxidative capacity, but as hypertrophy progresses to HF, mitochondrial function is gradually impaired [109]. Mitochondrial alterations and dysfunction have been linked to cardiac remodeling including morphology, FAO, ATP synthesis, biogenesis, ROS, and mitophagy.

It has been widely accepted that pressure overload–induced cardiac remodeling alters the mitochondrial morphology in size, volume, and numbers. For example, the mitochondria were found to be swollen, with degraded mtDNA and altered cristae structures in HCM model in pigs [110]. There were distorted cristae and reduced mitochondrial density and volume in a pressure overload–induced cardiac hypertrophic mouse model without difference in mitochondrial numbers between the hypertrophic hearts and the sham control [111]. Despite these evidence from animal models, observations from electron microscopy show remarkable variabilities in HF patients of cardiomyopathy in terms of the mitochondrial numbers, size, and matrix density [112].

In addition, in the pressure overloaded heart, the fuel that drives mitochondria to synthesize ATP switches from FA to glucose, which causes lesser ATP production and depletion in cellular energy. In normal physiology, the uptake of FAs involves the conjugation of FA to acetyl CoA (FA-CoA). FA-CoA enters the mitochondrial matrix and is metabolized by the beta oxidation process through the carnitine shuttle, CPT-1 and CPT-2 [113]. In the pressure overload heart, FAO rate is reduced, along with the decrease in mRNA expression of CPT-1 [114–116]; however, some report it to be unchanged [113]. The variable data might be due to the varying degrees of hypertrophy in different animals [113].

Furthermore, pressure overload–induced cardiac remodeling also affects mitochondrial biogenesis. In response to metabolic status of the cell, the mitochondria undergo controlled cycles of biogenesis with fusion and fission. The processes of the fusion and fission are well regulated by PGC-1α, which then regulates ERRα to act on the group of guanosine triphosphatases (GTPases). Fusion involves mitofusin proteins (MFN 1 and 2) in the outer mitochondrial membrane and optical atrophy protein 1 (OPA1) in the IMM. The fusion process is switched on to balance the mitochondrial membrane potential and allows for the exchange of matrix components, as well as damaged mtDNA [117]. Fission, on the other hand, allows for more mitochondria to be distributed further to release cytochrome c during apoptosis and mitochondrial degradation by mitophagy. Fission occurs through dynamin-1-like protein (DRP1), mitochondrial fission factor (MFF), and adapter protein mitochondrial fission 1 (FIS1). In physiological hypertrophy, PGC-1α activates biogenesis to meet the demands of the heart [77]. At early stages of pathological hypertrophy, mitochondrial biogenesis increases, and mitochondrial numbers increase, but as hypertrophy worsens to HF, PGC-1α expression is downregulated and biogenesis activity is impaired [79, 118]. In addition, as hypertrophy transits to HF, the expression of OPA1 is reduced and mitochondria become small and fragmented. Furthermore, in decompensated hypertrophy and HF, the mitochondrial biogenesis also declines due to depletion of ATP synthesis, which then halts the increase in new mitochondria in the cardiomyocyte [109].

uncoupling that in turn increases O2

drial uncoupling causes the rise in O2

**3.5. Genetic mitochondrial heart disease**

increase of mitochondrial O2

consumption. The series of events begins with the increased

Mitochondria and Heart Disease

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http://dx.doi.org/10.5772/intechopen.72611

consumption, the ATP production will not be increased.

consumption, which promotes the activation of FAO. As mitochon-

availability and delivery of FA that forces the mitochondria to increase FA uptake. This stimulates the increase in ROS production [129]. ROS generation activates the uncoupling proteins (UCs) and promotes proton leak via ANT. The increase in mitochondrial uncoupling propagates the

This reduces the cardiac efficiency of the cell in the generation and usage of energy, which subsequently reduces the provision of ATP for the cell and leads to contractile dysfunction. Thus, this is the link between the type 2 diabetes mechanism merging with contractile dysfunction and development of muscle pathology, with diastolic dysfunction and left ventricular hypertrophy.

Genetic MD can be caused by a mutation in either the mtDNA or the nDNA [130, 131]. MDs arising from mtDNA are more prevalent in adults, whereas diseases arising from nDNA tend to be more prevalent in infants and children [132]. MDs can also be classified by the function of the proteins involved in the disease. For example, MDs have been found to be associated with the mutations in genes that encode subunits of the ETC complexes [130] and ATP synthase [133, 134], ancillary proteins that participate in the assembly, transport, and function of the ETC complexes, or the regulatory proteins that control activities of the mitochondria [130, 131]. In addition, mutations have been described in gene-encoding proteins that synthesize cardiolipin, an integral part of the inner mitochondrial membrane [135, 136]. The most frequently identified biochemical abnormalities are deficiencies in NADH-coenzyme Q (CoQ)

The mitochondrion is a unique organelle as it possesses its own DNA system. While mutated DNA can affect any organ, the presence of the mtDNA mutations in highly metabolic tissues, such as brain, heart, skeletal muscle, and eyes, exhibits a more severe and progressive prognosis. Patients with the known mitochondrial mutation of m.3243A > G develop early death, whereas if this mutation has a cardiac cause, sudden deaths would occur [137]. A healthy individual may possess mutated DNA, but the onset of the disease will not be obvious until a certain mutation threshold of ~60–90% is present [138]. Inheritance of mtDNA occurs only through the maternal line with single, large-scale deletions being rare and the point mutations frequently transmitted [139].

Cross-sectional studies have shown that specific mitochondrial mutations have been presented with a certain cardiac phenotype, and cardiac disorders could inherit different mtDNA mutations [140]. For example, there are inherited familial cardiomyopathies (in both children and adult) linked to mutations in the mtDNA [139, 141]. Mutation m.1555A > G mt-rRNA has only been associated with restrictive cardiomyopathy [142]. Conversely, up to 40% of MD patients have HCM [143]; atrioventricular (AV) block is one of the manifestations of Kearns-Sayre syndrome (KSS) that is due to the large-scale deletions in the mtDNA [143]. The symptoms of HCM patients who have sarcomeric protein gene mutations differ from the those of MD patients who developed HCM. Generally, these MD patients who develop HCM have left ventricular dysfunction but no left ventricular outflow tract obstruction [144, 145]. Another cardiomyopathy-presenting phenotype that is less common in the MD patients is DCM. The

reductase (complex I) and cytochrome-c oxidase (complex IV) [135, 136].

echocardiographic findings showed slow progression of disease [146, 147].

Moreover, cardiac hypertrophy also affects the energetic cross-talk between mitochondria and other organelles to transfer ATP. There is direct communication between the mitochondria and the ATPases of the myofibrils and the SR [119]. Muscle mitochondria in its ordered bundled organization around the myofibrils and the SR are highly clustered at regions of high-energy demand where there is a tightly regulated ATP/ADP ratio [69]. In the pressure overload–induced hypertrophic heart, the direct channeling of ATP within the high-energy demand sites becomes weakened due to the decrease in mitochondrial content and numbers [69, 119]. In addition, mitophagy is activated in pressure overloaded cardiomyocytes due to the increased cellular damage from mitochondrial dysfunction. The causative factors of autophagy in cardiac hypertrophy are complex. Although low baseline autophagy allows the cardiomyocytes to adapt to hypertrophic demands, exacerbation of autophagy promotes hypertrophic contractile dysfunction [120].

In summary, pressure overload causes cardiac remodeling through disruption of the cell signaling pathway, altering the mitochondrial morphology in size, volume, and numbers, regulating the mitochondrial biogenesis and affecting the energetic cross-talk between mitochondria and other organelles to transfer ATP for utilization by the cardiomyocyte or mitophagy. These changes further lead to the failing of the myocardium.
