*3.1.5. Excess generation of ROS*

The respiratory chain regularly generates ROS in the form of O2 ·−, which can initiate the formation of other ROS such as OH, peroxynitrite, and H2 O2 . These O2 ·− are not able to easily 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 structural roles. In a canine model of HF and HF patient blood samples, O<sup>2</sup> ·− production by 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 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 kinase C, Jun N-terminal kinase, and mitogen-activated protein kinase [94, 102].

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

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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

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

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

continue to increase, leading to cell necrosis and apoptosis.

degrees of hypertrophy in different animals [113].

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

including morphology, FAO, ATP synthesis, biogenesis, ROS, and mitophagy.

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 efficiency of ATP production in cardiac mitochondria.
