Preface

The cell has a dynamic and complex architecture; therefore, it is not in equilibrium with its environment. The environment constantly disrupts this dynamic and complex harmony. For cell maintenance, cells must absorb different types of energy from their environment and convert this energy into usable chemical forms. The mitochondrion plays a major role in supporting cellular homeostasis and formalizes the physiology of a cell as the most signifi‐ cant energy producer in aerobes. It also participates in cell death mechanisms. Therefore, mitochondrial dysfunction is implicated in the mode of action of many harmful factors for cells such as drugs and environmental contaminants, dysfunction of the oxygen transport system, malnutrition, intense exercise, and genetic variations.

Multicellular organisms need oxygen to execute chemical transformations for ATP utiliza‐ tion and production as an energy transducer, and they need a pump for oxygen transport to the cells in hypoxic environments of their bodies. Heart function depends on continuous en‐ ergy supply, and therefore a complex mitochondrial network. Any factor affecting the mito‐ chondrial network will produce heart-related diseases and heart failure. Dr Stoll et al. tried to explain the role and the mechanism of mitochondria in the development of heart disease, and the progress in clinical diagnosis and treatments on a mitochondrial basis in recent studies. They proposed that further studies are required to confirm the effectiveness and toxicity of metabolic-modulating drugs and mitochondria-targeting antioxidants. As ex‐ plained in this chapter, changes in substrate utilization mechanisms should be solved for further understanding in developing effective treatment strategies against heart failure. Drs Bruns and Walker focused on the mechanism of right ventricular failure, which is less com‐ mon than the left ventricle failure. Both are mitochondria-related pathologies. A detailed ex‐ planation of the embryological, physiological, and pathophysiological differences between left and right ventricles is presented in their chapter in the view of recent studies. They re‐ ported that there is no right ventricle failure-targeted therapy and the current approach is extrapolating the therapeutic interventions for the left ventricular failure to the right one. However, there are some recent considerations to develop an effective therapy for right ven‐ tricle failure with further evaluations. Mitochondria accumulate the damaged and/or modi‐ fied proteins and mitochondrial DNA (mtDNA) during their life cycles. Mitophagy is an important physiological component for mitochondrial turnover to eliminate damaged or dysfunctional mitochondria to prevent further risk to the cell, especially to avoid unregulat‐ ed reactive oxygen formation. The healthy heart needs a fine balance between mitophagy and mitochondriogenesis; however, accumulation of damaged proteins and altered proteo‐ stasis in mitochondria is an important factor in age-related diseases of the heart. Dr Tatarko‐ va et al. have detailed the current knowledge on the physiological and biochemical changes in the mitochondrial functioning of the aging heart. They proposed that the development of restoration strategies against changed protein machinery should be beneficial against agerelated disorders, especially heart-related disorders.

action mapping of mitochondrial trafficking proteins. They proposed that the adequate de‐ scription of the modulation of the mitochondrial network will be useful to develop effective strategies against neurodegenerative diseases. However, this explanation will also be used for the treatment of all the mitochondrial-related diseases. In the other two chapters of the book, authors focused on the mitochondrial transport proteins and their roles in the patho‐ genesis of mitochondrial diseases. Dr Rosenberg et al. defined the role of the 18 kDa translo‐ cator protein (TSPO) in mitochondrial pathologies exemplified by the traumatic brain injury model. Nuclear-encoded proteins located on/in the inner and outer mitochondrial mem‐ branes have an interactive role in the proper functioning of the mitochondrion to balance the required amounts of intermediates between two sides of the mitochondrial membranes. Their interaction can also be useful to determine the fate of a cell. Therefore, their contribu‐ tion in mitochondrial physiology and pathophysiology is discussed in the chapter by Dr Vaskova et al. They concluded that the definition of mitochondrial transport mechanisms could contribute to better diagnosis and treatment of metabolic disorders. In another chap‐ ter, Dr Kaya et al. focused on the iron-sulfur cluster assembly proteins that have a role in the assembly of some of the inner membrane localized ETC and some of the cytosolic and matri‐ cial proteins. Their inheritance is carried out by nuclear DNA, and some recessive inheri‐ tance modes are inhibited with multiple mitochondrial dysfunctions syndrome characterized by various symptoms. Authors listed the case studies related to the inheri‐

Preface XI

The mitochondrion is also a key player in the mode of action of drugs and environmental toxicants. These chemicals interfere with the mitochondrial function via interaction with mi‐ tochondrial structures that play a role in different layers of mitochondrial homeostasis. Dr Guven et al. discussed the adverse effects of pyrethroids on mitochondrial mechanism as an example of environmental toxicants and doxorubicin as an example of therapeutic agents. They concluded that the most pronounced effects of these agents on mitochondria are the excessive production of reactive oxygen and the disruption of calcium homeostasis via di‐ rect and/or indirect pathways. Dr Twaroski et al. introduced their recent studies related to the role of the neurodegenerative potential of ketamine in developing neurons derived from human embryonic stem cells. Ketamine can induce the neuroapoptosis and can alter the mi‐ tochondrial ultrastructure through the dysregulated intracellular calcium/microRNA path‐ way. Collectively, their results put forward the safety of anesthesia, especially in pediatric patients. Dr Busanello et al. presented a well-defined scheme about the toxicity of statins, which are the most prevalent cholesterol-lowering agents. After the presentation of mito‐ chondrial toxicity of these agents, they proposed the coadministration of antioxidants specif‐ ically the coenzyme Q10 against the statins' toxicity. As a widespread legal drug, ethanol also targets mitochondrial function and the general mechanism of ethanol toxicity where the mitochondrion is the central mediator is discussed with different consumption scenarios in the chapter by Dr Tapia-Rojas et al. They concluded that the neuronal sites related to the ethanol dependence, learning, and memory are particularly vulnerable toward ethanol tox‐ icity; therefore, knowing all the events that induce mitochondrial dysfunction leads to the development of effective strategies against the toxicity observed in different patterns of

An entirely different role of mitochondria can be seen in virus infections. Because the fate of a cell is generally imposed by mitochondrial events, viruses target the mitochondria to in‐ crease their survival in their host cells. Interestingly, inheritance materials of these patho‐

tance of iron-sulfur clustering assembly proteins.

ethanol consumption.

Mitochondrial dysfunction can also be seen in many pathophysiological situations, for exam‐ ple, tumor progression. Therefore, there are recent studies to control cancer cells via mito‐ chondrial component targeting. Drs Paranagama and Kita presented their recent study that defines the complex II of electron transport chain targeted therapy against cancer cells. Ac‐ cording to their results, Atpenin A5, a complex II Q site inhibitor, elevates the reactive oxygen formation at this site in cancer cells while there is no effect in healthy cells. They hypothesized that there is a difference at this site via post-translational modification between healthy and cancer cells. Although cancer is known to be a genetic disorder, it has recently and predomi‐ nantly been accepted as a metabolic disease. Moreover, Dr Uchiumi et al. have explained can‐ cer as a transcriptional disease. They described the general scheme of mitochondrial dysfunction and the characteristic properties of the genes that have a role in this process. The relationship between the metabolic status, specially designated as NAD+ /NADH ratio, and the transcriptional profile of these genes has been explained in detail in the progression of cancer and aging. Finally, a list of possible genes to be targeted to improve mitochondrial functions and then to convert the cancer cells into the normal ones is provided.

Because of its ancestral bacterial origin, damage-associated molecular patterns are seques‐ tered within the mitochondrion, and their releases trigger the sterile innate immune re‐ sponses. This type of pathology is significant especially in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Dr Esteves et al. described innate immune responses observed in these neurodegenerative diseases and the interplay between innate immunity and mitochondria. They concluded that a better understanding of the con‐ tribution of mitochondria in neuroinflammatory processes and the exploration of markers would be useful to prevent and treat these disorders.

A mitochondrion contains different components in a delicate balance to produce energy from substrates and to decide the fate of a cell. While most of the proteins of the mitochond‐ rion are encoded in the nuclear DNA, mtDNA encodes 13 genes participating in the electron transfer chain (ETC). The ETC is localized in the inner membrane, while inner and outer mitochondrial membranes contain many proteins to transport ATP, substrates, Ca2+, reactive oxygen, etc. from the other parts of a cell. The proper functioning of ETC and trafficking proteins is vital and their deficiency or failure causes inadequate energy production, abnor‐ mal production of reactive oxygen, and then cell death. Dr Nowak reported that 354 mito‐ chondrial proteins are phosphoproteins, and their phosphorylation leads to the progression of mitochondrial damage depending on their phosphorylation site and the kinase as a cata‐ lyzer in the context of ischemia/reperfusion injury. She carefully reviewed and grouped the phosphoproteins according to their function in a mitochondrion. Therefore, mitochondrialrelated kinases may be a potential therapeutic target for the treatment of ischemic injury. There is a dynamic relationship between the cytoskeleton and mitochondrial proteins for effective energy production, and compensating the damaged parts of mitochondrial struc‐ tures, they reunite, which is named fusion. On the other hand, denser mitochondrial dam‐ age causes the splitting of mitochondria called fission. In all these situations, the mitochondrial morphology is changed. Pathophysiological conditions such as cardiovascu‐ lar, neurodegenerative, metabolic, tumor progression, etc. cause the change in mitochondri‐ al dynamics and therefore morphology. Dr Sripathi et al. presented their recent work on the pathophysiologic dynamics of mitochondria in age-related macular degeneration via inter‐

action mapping of mitochondrial trafficking proteins. They proposed that the adequate de‐ scription of the modulation of the mitochondrial network will be useful to develop effective strategies against neurodegenerative diseases. However, this explanation will also be used for the treatment of all the mitochondrial-related diseases. In the other two chapters of the book, authors focused on the mitochondrial transport proteins and their roles in the patho‐ genesis of mitochondrial diseases. Dr Rosenberg et al. defined the role of the 18 kDa translo‐ cator protein (TSPO) in mitochondrial pathologies exemplified by the traumatic brain injury model. Nuclear-encoded proteins located on/in the inner and outer mitochondrial mem‐ branes have an interactive role in the proper functioning of the mitochondrion to balance the required amounts of intermediates between two sides of the mitochondrial membranes. Their interaction can also be useful to determine the fate of a cell. Therefore, their contribu‐ tion in mitochondrial physiology and pathophysiology is discussed in the chapter by Dr Vaskova et al. They concluded that the definition of mitochondrial transport mechanisms could contribute to better diagnosis and treatment of metabolic disorders. In another chap‐ ter, Dr Kaya et al. focused on the iron-sulfur cluster assembly proteins that have a role in the assembly of some of the inner membrane localized ETC and some of the cytosolic and matri‐ cial proteins. Their inheritance is carried out by nuclear DNA, and some recessive inheri‐ tance modes are inhibited with multiple mitochondrial dysfunctions syndrome characterized by various symptoms. Authors listed the case studies related to the inheri‐ tance of iron-sulfur clustering assembly proteins.

restoration strategies against changed protein machinery should be beneficial against age-

Mitochondrial dysfunction can also be seen in many pathophysiological situations, for exam‐ ple, tumor progression. Therefore, there are recent studies to control cancer cells via mito‐ chondrial component targeting. Drs Paranagama and Kita presented their recent study that defines the complex II of electron transport chain targeted therapy against cancer cells. Ac‐ cording to their results, Atpenin A5, a complex II Q site inhibitor, elevates the reactive oxygen formation at this site in cancer cells while there is no effect in healthy cells. They hypothesized that there is a difference at this site via post-translational modification between healthy and cancer cells. Although cancer is known to be a genetic disorder, it has recently and predomi‐ nantly been accepted as a metabolic disease. Moreover, Dr Uchiumi et al. have explained can‐ cer as a transcriptional disease. They described the general scheme of mitochondrial dysfunction and the characteristic properties of the genes that have a role in this process. The

the transcriptional profile of these genes has been explained in detail in the progression of cancer and aging. Finally, a list of possible genes to be targeted to improve mitochondrial

Because of its ancestral bacterial origin, damage-associated molecular patterns are seques‐ tered within the mitochondrion, and their releases trigger the sterile innate immune re‐ sponses. This type of pathology is significant especially in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Dr Esteves et al. described innate immune responses observed in these neurodegenerative diseases and the interplay between innate immunity and mitochondria. They concluded that a better understanding of the con‐ tribution of mitochondria in neuroinflammatory processes and the exploration of markers

A mitochondrion contains different components in a delicate balance to produce energy from substrates and to decide the fate of a cell. While most of the proteins of the mitochond‐ rion are encoded in the nuclear DNA, mtDNA encodes 13 genes participating in the electron transfer chain (ETC). The ETC is localized in the inner membrane, while inner and outer mitochondrial membranes contain many proteins to transport ATP, substrates, Ca2+, reactive oxygen, etc. from the other parts of a cell. The proper functioning of ETC and trafficking proteins is vital and their deficiency or failure causes inadequate energy production, abnor‐ mal production of reactive oxygen, and then cell death. Dr Nowak reported that 354 mito‐ chondrial proteins are phosphoproteins, and their phosphorylation leads to the progression of mitochondrial damage depending on their phosphorylation site and the kinase as a cata‐ lyzer in the context of ischemia/reperfusion injury. She carefully reviewed and grouped the phosphoproteins according to their function in a mitochondrion. Therefore, mitochondrialrelated kinases may be a potential therapeutic target for the treatment of ischemic injury. There is a dynamic relationship between the cytoskeleton and mitochondrial proteins for effective energy production, and compensating the damaged parts of mitochondrial struc‐ tures, they reunite, which is named fusion. On the other hand, denser mitochondrial dam‐ age causes the splitting of mitochondria called fission. In all these situations, the mitochondrial morphology is changed. Pathophysiological conditions such as cardiovascu‐ lar, neurodegenerative, metabolic, tumor progression, etc. cause the change in mitochondri‐ al dynamics and therefore morphology. Dr Sripathi et al. presented their recent work on the pathophysiologic dynamics of mitochondria in age-related macular degeneration via inter‐

/NADH ratio, and

relationship between the metabolic status, specially designated as NAD+

functions and then to convert the cancer cells into the normal ones is provided.

related disorders, especially heart-related disorders.

X Preface

would be useful to prevent and treat these disorders.

The mitochondrion is also a key player in the mode of action of drugs and environmental toxicants. These chemicals interfere with the mitochondrial function via interaction with mi‐ tochondrial structures that play a role in different layers of mitochondrial homeostasis. Dr Guven et al. discussed the adverse effects of pyrethroids on mitochondrial mechanism as an example of environmental toxicants and doxorubicin as an example of therapeutic agents. They concluded that the most pronounced effects of these agents on mitochondria are the excessive production of reactive oxygen and the disruption of calcium homeostasis via di‐ rect and/or indirect pathways. Dr Twaroski et al. introduced their recent studies related to the role of the neurodegenerative potential of ketamine in developing neurons derived from human embryonic stem cells. Ketamine can induce the neuroapoptosis and can alter the mi‐ tochondrial ultrastructure through the dysregulated intracellular calcium/microRNA path‐ way. Collectively, their results put forward the safety of anesthesia, especially in pediatric patients. Dr Busanello et al. presented a well-defined scheme about the toxicity of statins, which are the most prevalent cholesterol-lowering agents. After the presentation of mito‐ chondrial toxicity of these agents, they proposed the coadministration of antioxidants specif‐ ically the coenzyme Q10 against the statins' toxicity. As a widespread legal drug, ethanol also targets mitochondrial function and the general mechanism of ethanol toxicity where the mitochondrion is the central mediator is discussed with different consumption scenarios in the chapter by Dr Tapia-Rojas et al. They concluded that the neuronal sites related to the ethanol dependence, learning, and memory are particularly vulnerable toward ethanol tox‐ icity; therefore, knowing all the events that induce mitochondrial dysfunction leads to the development of effective strategies against the toxicity observed in different patterns of ethanol consumption.

An entirely different role of mitochondria can be seen in virus infections. Because the fate of a cell is generally imposed by mitochondrial events, viruses target the mitochondria to in‐ crease their survival in their host cells. Interestingly, inheritance materials of these patho‐

gens encode different mitochondrion-resident proteins to control the cell functions. However, some viral proteins act as pro-apoptotic depending on the cellular environment according to Dr Reshi et al. The most vulnerable parameter in a virus infection is the loss of mitochondrial membrane potential, for which the exact mechanism is not currently under‐ stood. They concluded that more information on the virus-host cell interaction is needed to treat challenging virus infections.

Dr Mooga et al. discussed the role of estrogen‑a pleiotropic hormone‑and its receptors in inflammation, cardiovascular diseases, neurodegeneration, aging, and cancer in the view of mitochondrial regulation. Gender-specific differences and age-related challenges in females are well-explained in this chapter. Several cytoprotective mechanisms of estrogen and its receptors support mitochondrial function such as mitochondrial respiration and ATP pro‐ duction, attenuation of reactive oxygen formation, and inhibition of mitochondrial cell death pathways essential in the normal physiological and pathophysiological conditions. On the contrary, these events are also crucial in the estrogen-related promotion of normal and neo‐ plastic breast cancer cells.

Collectively, as the powerhouse of a cell, the mitochondrion is one of the targets of thera‐ peutic interventions because of its role in normal physiologic and pathophysiologic condi‐ tions. Different layers of mitochondrial mechanisms become an essential part of a specific pathophysiologic condition. However, reactive oxygen formation, altered calcium homeo‐ stasis, and mitochondrial morphology are the most common indicators of mitochondrial dysfunction. There are still many unknowns in inner mitochondrial mechanisms and their interplay and dependence with other components of the cell such as endoplasmic reticulum, cytosol, plasma membrane, and nuclear DNA. Therefore, research on mitochondrial diseas‐ es, determination of specific markers, and development of effective treatments will be a competing area in the medical and biological fields.

> **Eylem Taskin** Nigde Omer Halisdemir University Medical Faculty Physiology Department Nigde, Turkey

#### **Celal Guven**

**Section 1**

**Mitochondrial Dysfunction and Cardiovascular**

**Diseases**

Nigde Omer Halisdemir University Medical Faculty Biophysics Department Nigde, Turkey

#### **Yusuf Sevgiler**

Adiyaman University Faculty of Science and Letters Department of Biology Adiyaman, Turkey **Mitochondrial Dysfunction and Cardiovascular Diseases**

gens encode different mitochondrion-resident proteins to control the cell functions. However, some viral proteins act as pro-apoptotic depending on the cellular environment according to Dr Reshi et al. The most vulnerable parameter in a virus infection is the loss of mitochondrial membrane potential, for which the exact mechanism is not currently under‐ stood. They concluded that more information on the virus-host cell interaction is needed to

Dr Mooga et al. discussed the role of estrogen‑a pleiotropic hormone‑and its receptors in inflammation, cardiovascular diseases, neurodegeneration, aging, and cancer in the view of mitochondrial regulation. Gender-specific differences and age-related challenges in females are well-explained in this chapter. Several cytoprotective mechanisms of estrogen and its receptors support mitochondrial function such as mitochondrial respiration and ATP pro‐ duction, attenuation of reactive oxygen formation, and inhibition of mitochondrial cell death pathways essential in the normal physiological and pathophysiological conditions. On the contrary, these events are also crucial in the estrogen-related promotion of normal and neo‐

Collectively, as the powerhouse of a cell, the mitochondrion is one of the targets of thera‐ peutic interventions because of its role in normal physiologic and pathophysiologic condi‐ tions. Different layers of mitochondrial mechanisms become an essential part of a specific pathophysiologic condition. However, reactive oxygen formation, altered calcium homeo‐ stasis, and mitochondrial morphology are the most common indicators of mitochondrial dysfunction. There are still many unknowns in inner mitochondrial mechanisms and their interplay and dependence with other components of the cell such as endoplasmic reticulum, cytosol, plasma membrane, and nuclear DNA. Therefore, research on mitochondrial diseas‐ es, determination of specific markers, and development of effective treatments will be a

**Eylem Taskin**

Medical Faculty

Nigde, Turkey **Celal Guven**

Medical Faculty

Nigde, Turkey **Yusuf Sevgiler** Adiyaman University

Physiology Department

Biophysics Department

Faculty of Science and Letters Department of Biology Adiyaman, Turkey

Nigde Omer Halisdemir University

Nigde Omer Halisdemir University

treat challenging virus infections.

XII Preface

plastic breast cancer cells.

competing area in the medical and biological fields.

**Chapter 1**

**Provisional chapter**

**Mitochondria and Metabolism in Right Heart Failure**

Heart failure (HF) is a clinically complex and heterogenous disease characterized by an inability of the heart to pump sufficient blood to the periphery. As such, it has historically been thought of and studied as a disease of the left ventricle (LV). While LV failure is the most common form of HF, it is the ability of the right heart to function that predicts survival in many clinical settings. Extrapolation of mechanisms of left HF to the right ventricle (RV) has yet to prove fruitful in identification of therapeutic approaches, in large part due to a lack of basic mechanistic understanding of the RV which is embryologically, anatomically, and physiologically distinct from the LV. The failing LV is characterized by mitochondrial dysfunction and a metabolic switch, both of which contribute to an energetically starved heart with poor contractile ability. These mechanisms, however, are far less described in the failing RV. The purpose of this chapter is to present the current literature examining the role of mitochondria and metabolism in the healthy right heart, treatments to target deficits in the failing RV, and to identify knowledge gaps for future

**Keywords:** heart failure, right ventricle, mitochondria, metabolism, ventricular dysfunction,

Cardiovascular disease is the leading cause of death worldwide, of which heart failure (HF) constitutes a growing public health concern. In the United States alone, close to 6 million individuals currently suffer from HF, accounting for nearly one of out every nine deaths [1]. Morbidity and mortality from HF are high, with 50% mortality within the first 5 years of diagnosis. HF is also a financial burden on the healthcare system, with direct costs estimated at \$32 billion per year in the United States [2], roughly 2–3% of total global healthcare spending.

**Mitochondria and Metabolism in Right Heart Failure**

DOI: 10.5772/intechopen.70450

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Danielle R. Bruns and Lori A. Walker

Danielle R. Bruns and Lori A. Walker

http://dx.doi.org/10.5772/intechopen.70450

**Abstract**

Additional information is available at the end of the chapter

research in this clinically important area.

pulmonary hypertension

**1. Introduction**

Additional information is available at the end of the chapter

**Provisional chapter**
