The heart is one of the most energy consuming organs in the human body and largely covers its energy demand by fatty acid oxidation in the mitochondria. Mitochondria are double membrane surrounded organelles and harbor β-oxidation enzymes, the Krebs cycle and the respiratory chain for energy conversion. Many of these essential functions are associated with mitochondrial membranes, which have a unique lipid composition, with cardiolipin (CL) as the hallmark mitochondrial phospholipid. Inherited defects in the biosynthesis of CL, as in Barth Syndrome (BTHS), cause mitochondrial dysfunction and severely affect heart function. Using a mouse model for BTHS and patient iPSC derived cardiomyocytes, we have shown previously that CL deficiency in BTHS causes structural remodeling of the mitochondrial respiratory chain and an increase in reactive oxygen species. Redox homeostasis is another essential function of the mitochondria. Increased cardiac workload is associated with an elevated consumption of reduction equivalents, which must be compensated by an increase in mitochondrial metabolism. Calcium signals ensure the energetic coupling of mitochondrial and cytosolic metabolism. In Barth syndrome, this coupling is disrupted by a defect in the mitochondrial calcium uniporter (MCU). Here we show, that defects in energy and redox homeostasis causes significant changes in cardiac metabolism. The healthy heart meets its energy demand mainly through fatty acid metabolism (60-80%). Using in vivo PET-CT imaging, we were able to show a considerable reduction in fatty acid oxidation and an increase in glucose metabolism in Barth syndrome. In contrast, we find compensatory alterations in the glutamate metabolism and glutathione biosynthesis. Transcriptome analyzes of the BTHS heart muscle revealed a stress-induced retrograde signaling pathway that plays a major role in the compensatory transformation of metabolism. Targeted interventions in the cell metabolism enable new strategies for therapeutic intervention in cardiomyopathies with mitochondrial dysfunctions.