The heart has the largest energy demand in the body and requires constant energy supply, provided by oxidative phosphorylation in the mitochondria. The balance between energy supply and demand is at threat in heart failure, where cardiac remodeling causes increased energy demand. At the same time, alterations in mitochondria cause significant changes in cardiac metabolism and impair energy supply. Structural and functional alterations in mitochondria are implicated in defects in energy conversion and redox homeostasis and in the development of heart failure. Mitochondrial defects result in increased reactive oxygen species (ROS), alterations of Ca2+ homeostasis and changes in mitochondrial dynamics. Mitochondrial alterations enforce changes in metabolism, affect posttranslational protein modification and changes cellular transcription pattern. In heart failure, alterations in the mechano-energetic coupling are key drivers of cardiac dysfunction and arrhythmias. Therapeutic strategies aim to reduce energy demand but novel concepts, directly targeting mitochondrial metabolism are emerging.
Metabolic alterations and defects in mitochondrial structure and function in heart failure have been well described. However, the molecular mechanisms how mitochondrial dysfunction affects cardiac function is only poorly understood. We would like to understand how defective energy conversion and redox homeostasis directly link to cardiac dysfunction and arrhythmias and how metabolic alterations link to cardiac remodeling. How can we use novel models, including induced pluripotent stem cell derived cardiomyocytes, to reveal the mechanisms by which mitochondrial dysfunctions trigger adaptive or maladaptive responses. A detailed understanding of the pathological mechanisms will guide the way to new strategies for therapeutic intervention.
The scope of this Research Topic is to reveal the molecular mechanisms, how mitochondrial dysfunction affects cardiac function and which therapeutic strategies can be deviated in this context. Researchers are invited to submit their original research articles, reviews, mini-reviews or commentaries to contribute to the following questions:
• How does impaired mitochondrial calcium handling and altered redox homeostasis affect cardiac function in aging and heart failure?
• What are the mechanistic implications of mitochondrial dynamics and changes in oxidative phosphorylation in aging and heart failure?
• How do changes in cellular NAD+/NADH ratio affect cardiac function?
• Mechano-energetic coupling: How does defective energy conversion affect cardiac contraction cycle?
• How do inherited defects in mitochondria cause cardiomyopathies?
• How can we use stem cell derived cardiomyocytes to understand the involvement of metabolism in alterations of cardiac function?
• How does alterations in mitochondrial and cellular metabolism drive cardiac remodeling in aging and heart failure?
• How do mitochondrial retrograde signaling induce compensatory responses of the cell?
The heart has the largest energy demand in the body and requires constant energy supply, provided by oxidative phosphorylation in the mitochondria. The balance between energy supply and demand is at threat in heart failure, where cardiac remodeling causes increased energy demand. At the same time, alterations in mitochondria cause significant changes in cardiac metabolism and impair energy supply. Structural and functional alterations in mitochondria are implicated in defects in energy conversion and redox homeostasis and in the development of heart failure. Mitochondrial defects result in increased reactive oxygen species (ROS), alterations of Ca2+ homeostasis and changes in mitochondrial dynamics. Mitochondrial alterations enforce changes in metabolism, affect posttranslational protein modification and changes cellular transcription pattern. In heart failure, alterations in the mechano-energetic coupling are key drivers of cardiac dysfunction and arrhythmias. Therapeutic strategies aim to reduce energy demand but novel concepts, directly targeting mitochondrial metabolism are emerging.
Metabolic alterations and defects in mitochondrial structure and function in heart failure have been well described. However, the molecular mechanisms how mitochondrial dysfunction affects cardiac function is only poorly understood. We would like to understand how defective energy conversion and redox homeostasis directly link to cardiac dysfunction and arrhythmias and how metabolic alterations link to cardiac remodeling. How can we use novel models, including induced pluripotent stem cell derived cardiomyocytes, to reveal the mechanisms by which mitochondrial dysfunctions trigger adaptive or maladaptive responses. A detailed understanding of the pathological mechanisms will guide the way to new strategies for therapeutic intervention.
The scope of this Research Topic is to reveal the molecular mechanisms, how mitochondrial dysfunction affects cardiac function and which therapeutic strategies can be deviated in this context. Researchers are invited to submit their original research articles, reviews, mini-reviews or commentaries to contribute to the following questions:
• How does impaired mitochondrial calcium handling and altered redox homeostasis affect cardiac function in aging and heart failure?
• What are the mechanistic implications of mitochondrial dynamics and changes in oxidative phosphorylation in aging and heart failure?
• How do changes in cellular NAD+/NADH ratio affect cardiac function?
• Mechano-energetic coupling: How does defective energy conversion affect cardiac contraction cycle?
• How do inherited defects in mitochondria cause cardiomyopathies?
• How can we use stem cell derived cardiomyocytes to understand the involvement of metabolism in alterations of cardiac function?
• How does alterations in mitochondrial and cellular metabolism drive cardiac remodeling in aging and heart failure?
• How do mitochondrial retrograde signaling induce compensatory responses of the cell?
![Modeling of metabolic/mitochondrial cardiomyopathies (MCM) using human iPSC- cardiomyocytes (iPSC-CM) discussed in this review. MCM can be modeled in vitro by reprogramming somatic cells of MCM patients to iPSC and subsequent differentiation into iPSC-CM. IPSC harbour the genetic information of the patients and the disease. Cardiac dysfunctions studied via iPSC-CM include: I) Syndromes with cardiomyopathies caused by mutations in nuclear-encoded mitochondria-relevant genes: The Barth syndrome [mutation in TAFFAZIN (TAZ)] causes failed maturation of the mitochondrial cardiolipin. Friedreich’s ataxia [mutation in the FRATAXIN (FXN)] iPSC-CM demonstrate an impaired production of functional Fe-S clusters essential for the mitochondrial respiratory chain complexes I, II, III. Propionic acidemia [mutation in PROPIONYL-CoA CARBOXYLASE SUBUNIT alpha/beta (PCCA/PCCB)] results in decreased production of succinyl-CoA, an important intermediate of the mitochondrial tricarboxylic acid cycle (TCA). II) Cardiomyopathies caused by mutations of the circular mitochondrial DNA. Mutations in the Mt-RNR2 gene coding for mitochondrial ribosomal 16s-RNA result in hypertrophic cardiomyopathy (HCM). III) Syndromes with cardiomyopathies that originate from lysosomal storage defects. The Fabry syndrome [mutation in alpha-GALACTOSIDASE A (GLA)] manifests in increased glycolipid accumulation, whereas the Pompe syndrome [mutation in alpha-GLUCOSIDASE (GAA)] concludes in over-accumulation of glycogene.](https://www.frontiersin.org/_rtmag/_next/image?url=https%3A%2F%2Fwww.frontiersin.org%2Ffiles%2FArticles%2F1222986%2Ffmmed-03-1222986-HTML%2Fimage_m%2Ffmmed-03-1222986-g001.jpg&w=3840&q=75)
