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Retrograde signaling pathways and changes in cardiac metabolism induced by mitochondrial dysfunction in Barth syndrome

Subject Area Cell Biology
Biochemistry
Term from 2019 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 423600288
 
Final Report Year 2024

Final Report Abstract

The heart is one of the most energy demanding organs in the human body. Mitochondria are central organelles of the metabolism and provide the required energy by oxidative phosphorylation, while keeping toxic byproducts, called reactive oxygen species (i.e. hydrogen peroxide) in check. Many forms of inherited and acquired heart failure are associated with dysfunctional mitochondria, but the detailed molecular mechanisms, how mitochondria are involved in cardiac disease remains unresolved. We exemplify metabolic dysfunction in the heart with an inherited mitochondrial disease, called Barth Syndrome (BTHS). BTHS results in cardiomyopathy, skeletal myopathy and growth delay. The cardiomyopathy phenotype is associated with diastolic dysfunction, preserved ejection fraction, reduced contractile reserve and elevated arrhythmic contractions. BTHS is caused by a defect in the biosynthesis of the mitochondrial phospholipid Cardiolipin (CL), which plays an important role in the inner membrane. CL deficiency causes structural remodeling of the mitochondrial respiratory chain and reduced Krebs cycle activity. Moreover, defects in the mitochondrial calcium uniporter (MCU) ablates calcium mediated acceleration of mitochondrial metabolism and endangers the redox balance. We have previously shown, that defects in redox homeostasis and energy conversion cause arrhythmias and link to the inability to accelerate workload under exercise conditions. In order to substantiate the defect in energy conversion we show a defect in fatty acid oxidation, which provides most of the energy demand for the healthy heart. In this project we address, how retrograde signaling pathways induce metabolic alterations to compensate for mitochondrial dysfunction. We show in detail the activation of the integrated stress response (ISR), including the phosphorylation of the eukaryotic initiation factor (eIF2a). We address the molecular mechanism, by which mitochondrial dysfunction activates stress sensor kinases in the endo/sacroplasmatic reticulum. ISR induces gene expression of several transcription factors in parallel, including ATF3, ATF4 and ATF5. We show, that ATF4 activation in BTHS induces substantial changes in cardiac amino acid metabolism. Using carbon tracing experiments in vitro (iPSC cardiomyocytes) and in vivo (mouse model), we observe a compensatory upregulation of the serine pathway and the one carbon metabolism. ATF4 induces an increase in the activity of a cysteine transporter, resulting in a substantial elevation of cysteine uptake in the heart, which we measured by positron emission tomography (PET) of a cysteine radiotracer in vivo. These metabolic changes serve to enhance glutathione biosynthesis in order to compensate defects in redox homeostasis. ISR induced metabolic alterations also include elevated anaplerotic glutamine metabolism, supplementing the Krebs cycle and energy converting pathways. The knowledge of metabolic alterations provide new concepts for therapeutic interventions in mitochondrial cardiomyopathies, where no treatment options are currently available.

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