Activation of stress response signaling rewires cardiac metabolism in Barth syndrome
Jan Dudek (1),Ilona Kutschka (1), Edoardo Bertero (1), Christina Wasmus (1), Manuela Erk (1), Berkan Arslan (1), Paula Meier (1), Werner Schmitz (2), Peter Rehling (3), Ke Xiao (4), Thomas Thum (4), Lifeng Yang (5), Joshua Rabinowitz (6), Takahiro Higuchi (1), Christoph Maack (1)
1 Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, 97078 Würzburg
2 Department for Biochemistry and Molecular Biology, University of Würzburg, 97074 Würzburg
3 Department for Cellular Biochemistry, University of Göttingen, 37073 Göttingen
4 Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, 30625 Hannover
5 Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Rd., Shanghai 200031, China
6 Lewis-Sigler Institute for Integrative Genomics Princeton University Princeton, NJ 08544
To compensate for changing workload conditions in the heart, mitochondrial energy provision and redox homeostasis needs to be tightly coupled to energy demand. We have recently shown that defects in cardiolipin remodeling affects mitochondrial calcium signaling and compromises the metabolic adaptation in Barth syndrome. How mitochondrial defects are compensated by cellular metabolism is poorly understood. Here we analyzeβ-oxidation of fatty acids as the largest contributor to energy conversion in the heart. We report a severe reduction of enzymes involved in fatty acid transport and oxidation. Using in vivo PET-CT imaging, in a mouse model of Barth syndrome we find a substantial reduction of fatty acid oxidation in the diseased heart and an increase in glucose uptake. Lack of energy conversion from fatty acids triggers a substantial remodeling of cardiac metabolism. Metabolic remodeling in mice and in inducible pluripotent stem cell-derived cardiomyocytesis driven by a stress-induced retrograde signaling pathway. The transcription factor ATF4 induces changes at transcriptional, protein and metabolic flux level. Metabolic changes included serine of the serine biosynthesis from glucose, conversion of serine into glycine and glutamine and cysteine uptake. Increased folate cycle activity link to glutathione biosynthesis, which serves to compensate defects in redox homeostasis. Anaplerotic refilling of TCA cycle maintains mitochondrial function and energy conversion. In conclusion, activation of Atf4 rewires cardiac metabolism in Barth syndrome.
