*3.1.1. Reduction of ATP synthesis*

enzymatic function has been reported. Within cardiomyocytes, the interfibrillar mitochondria consume less oxygen and show a decrease in the ETC enzyme activity, particularly complexes III and IV during aging [53, 54]. This decrease in enzyme activity may lead to the lowered abil-

Furthermore, mitochondrial abnormalities have been proposed due to the increased mitochondrial production of ROS during aging. The rate of oxidative phosphorylation decreases with aging, allowing for increased leakage of electrons [48], these electrons are then able to interact with oxygen, generating superoxide anions and other forms of ROS. Excessive ROS formation has harmful consequences, including cellular dysfunction and cell death [48]. This high level of ROS is also able to oxidize mtDNA. Moreover, opening of the mPTP has been found to be changed in the heart during aging [55]. Increased opening of the mPTP may be

Although the pathophysiology of heart diseases is divergent, mitochondrial dysfunction appears to be a common mechanism that determines cardiac survival and function. Cardiac mitochondrial abnormalities include shifted metabolic substrate utilization, impaired mitochondrial ETC activity, increased formation of ROS, altered calcium homeostasis, and increased mPTP opening. Defects in mitochondrial structure and function have been found in association with cardiovascular diseases such as dilated and hypertrophic cardiomyopathy (DCM and HCM, respectively), cardiac conduction defects and sudden death, ischemic and alcoholic cardiomyopathy, and myocarditis. This section focuses on the changes of mitochondrial bioenergetics that are associated with cardiac survival and growth in heart diseases, including heart failure (HF), ischemia/reperfusion (I/R), pressure overload–induced cardiac hypertrophy and the cardiomyopathies in diabetes, and genetic mitochondrial diseases (MD).

HF is an end stage of many heart disorders and a complex chronic clinical syndrome. Although the causes of HF are variable, HF is viewed as an energy-mismatched disease [1, 56]. The first link between HF and mitochondrial dysfunction was described in 1962 in a guinea pig model with HF induced by an aortic restriction [57]. Since this observation, there has been growing interest in the investigation of mitochondrial function in failing hearts [58], and emerging evidence supports the concept that dysregulation of myocardial energetics is tightly associated

The heart requires large amounts of energy to facilitate its continuous contraction and relaxation cycles. HF occurs when the energy demand outweighs the energy supply. Any contributor that leads to HF is accompanied with a gradual but progressive decline in the activity of mitochondrial respiration, leading to diminished capacity for ATP production and subsequent progression of the heart to fail. Reciprocally, a failed heart reduces the blood and oxygen supply to the peripheral tissues and to the heart itself, further exacerbating the decline in cardiac energy production. On the other hand, the amount of ATP required from the mitochondria is increased to meet the abnormally enlarged myocardium size and failing function, augmenting

ity to meet the energy demands of the heart as aging ensues.

**3. Mitochondria in heart diseases**

38 Mitochondrial Diseases

**3.1. Mitochondrial dysfunction in HF**

with the development and progression of HF [1, 56, 59, 60].

linked to higher ROS levels and thus may be facilitating the aging process.

Like all the other cells, there are three energy systems that contribute to the production of ATP in cardiac muscles: phosphagen system (ATP-creatine phosphate cycling; high power, short duration), glycolysis (moderate power/short duration), and FAO (low power/long duration). Three energy systems can be selectively recruited, depending on the amount of oxygen available, as part of the cellular respiration process to generate the ATP for the cardiac muscles. Since the heart has a limited capacity for substrate storage, energy is required to rebuild or resynthesize it. The energy released from any of these three series of reactions is coupled with the energy requirements of the reaction that resynthesizes ATP.

ATP-CP system is the quickest way to resynthesize ATP. CP, like ATP, is stored in cardiac muscle cells and serves as the main energy store in myocardium. If oxygen is unavailable, the ATP-CP system does not use oxygen and does not produce lactic acid. This is the primary system behind the very short, powerful movements of the cardiac contraction and relaxation cycle. When CP is broken down, a large amount of energy is released. This energy released is coupled to the energy requirement necessary for the resynthesis of ATP. CP can easily diffuse through the inner mitochondrial membrane to the cytosol to generate ATP from ADP catalyzed by the cytosolic CK (cytoCK). Normal beating cardiomyocytes, even under variations of workload, maintain a constant level of ATP and CP in the cytosolic and mitochondrial compartments [58]. The CP/ATP ratio of 1.7–2.1 reflects normal mitochondrial ATP production and CK efficiency. This ratio has become a powerful index of the bioenergetics of the heart and its decrease has been reported in both the human and animal models of HF [61–65]. In HF patients and animal models, the total CK, as well as both the cytoCK and mitoCK, positively correlates with ejection fraction and can decrease as much as 50% [66–68]. It is observed that the decrease in CK activity, rather than the level of hypertrophy itself, is a hallmark of the transition from severe hypertrophy to HF [62, 69]. Interestingly, healthy myocardial cell size, myofibrillar and cytoskeletal organization, and positioning of the mitochondria near the SR allow for the ATP production in both mitochondrial and cytosolic regions and work concurrently to meet the energy demand [69]. However, in the failing hearts, the increase in myocardial cell size, the shrinkage of mitochondrial content, the alterations in microtubules, and the disorganization of cytoskeletal protein and their reduced expression contribute to decrease the efficiency of mitoCK and cytoCK for the energy transfer between the mitochondria and the cytosol [70–73].

The glycolysis system is the second-fastest way to resynthesize ATP. In the normal heart, pyruvate is converted into a metabolic intermediary molecule called acetyl coenzyme A (acetyl-CoA), which enters the mitochondria for oxidation and the production of more ATP. In the failing heart, the conversion to lactate occurs due to the greater demand for oxygen than the available supply. Although the catabolism of sugar supplies the necessary energy from which ATP is manufactured, it is only partially broken down when sugar is metabolized anaerobically. Only a few moles of ATP can be resynthesized from the breakdown of sugar as compared to the yield possible when oxygen is present. In addition, there is an increase in hydrogen ions due to the formation of lactic acid, causing the muscle pH to decrease. This leads to acidosis and the accumulation of other metabolites such as ADP, Pi , and potassium ions that may further induce the inhibition of specific enzymes involved in metabolism and muscle contraction.

these evidences of the cardiac pathologies that come from reduced mitochondrial FAO, the shift from FAO to glucose in the hypertrophied heart may be beneficial and adaptive for the short term. PPARα-null mice, for example, have reduced FAO efficiency, but the hearts showed no ventricular dysfunction. However, in a rat pressure overload model, when FAO was reactivated, the hearts developed ventricular dysfunction [88]. In addition, the degree and duration of the pathophysiological stimulus as well as the systemic metabolic state (e.g., levels of circulating lipids) may contribute to the consequence of alterations of FAO capacity in the pathogenesis of HF.

The reduction of energy production rate in dysfunctional mitochondria is also attributed by the dysregulation of Ca2+ homeostasis within the cardiomyocyte. Mitochondria act as a calcium sensor detecting the increase and decrease of the cytosolic Ca2+ to meet the needs of the cardiomyocyte. Ca2+ is transported into the mitochondria via MCU and out of the mitochondria via the sodium-calcium exchanger (NCX). Both the MCU and mitochondrial NCX are localized to the IMM. In normal physiological conditions, in the event of increased workload, the cytosolic Ca2+ is increased, triggering the opening of the MCU to transport Ca2+ into the mitochondrial matrix. The influx of the mitochondrial Ca2+ in the matrix increases the ATP synthase and the dehydrogenase activity of the citric acid cycle to generate more ATP [58]. Another transporter of Ca2+ into the mitochondria is the mPTP, which requires oxidative stress, elevated phosphate, and adenine nucleotide depletion to be opened. Increased uptake of Ca2+ into the mitochondria has been linked to cellular dysfunction and energy reduction [89, 90]. Also, the accumulation of Ca2+ in the mitochondria induces activation of the apoptotic and necrotic pathways [91]. In addition, in postmyocardial infarction HF mouse model, diastolic SR Ca2+ leak induces mitochondrial Ca2+ overload and dysfunction [92]. In HF, Ca/calmodulin-dependent protein kinase II (CamKII) has been involved in increasing mitochondrial Ca2+ uptake through the MCU and promotes mPTP opening and myocardial cell death [93].

Efficient mitochondrial capacity to meet the heart's workload also involves maintaining and protecting its biogenesis. It has been shown that the mitochondrial biogenesis was declined in failing heart, which is associated with the downregulation of the transcription factors such

permeate outside the mitochondria and become trapped within. Since mtDNA has no protective histones and a poor DNA repair system, mtDNA is more susceptible to damage and has a high mutation rate [58]. Presence of ROS generates oxidative stress and damage not only to DNA, but also to proteins of the cell, which include those in signaling of the mechanical and

the mitochondria is increased [95, 96]. The reduction of PGC-1α in HF has also been found to promote oxidative stress and mitochondrial damage [97]. Another source of ROS is one of the

O2

. These O2

·−, which can initiate the for-

Mitochondria and Heart Disease

41

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

·− are not able to easily

·− production by

The respiratory chain regularly generates ROS in the form of O2

structural roles. In a canine model of HF and HF patient blood samples, O<sup>2</sup>

mation of other ROS such as OH, peroxynitrite, and H2

*3.1.3. Dysregulation of Ca2+ homeostasis*

*3.1.4. Impaired mitochondrial biogenesis*

as NRF and ERRα [94].

*3.1.5. Excess generation of ROS*

The aerobic system includes the Krebs cycle and the ETC. Mitochondria are crucial for the working of the cardiomyocytes as these powerhouses provide the aerobic metabolism for the cardiomyocyte function. Reduced mitochondrial oxidative capacity has been observed in rodent HF models. The onset of HF is not an overnight process but a progression of continual abnormalities in the bioenergetics due to the disruption of metabolic regulatory signaling pathway or the lack of oxygen supply, which leads to failure in mitochondrial dysfunction and decline in ATP production.
