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

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Barth syndrome (BTHS) is an inherited form of cardiomyopathy, caused by a defect in the biogenesis of the mitochondrial phospholipid cardiolipin (CL). CL deficient cardiac mitochondria show a structural remodeling of the respiratory chain, a decreased respiration and an increased generation of reactive oxygen species (ROS). In this project, we will address the hypothesis that mitochondrial dysfunction is sensed by a retrograde signaling pathway and triggers an adaptive remodeling of cellular metabolism. Using the BTHS mouse model and patient derived iPSC cardiomyocytes (iPSC-CM) we will test the hypothesis that the induction of the integrated stress response pathway (ISR) and the stabilization of the stress induced transcription factor ATF5 is involved in changes in gene transcription. We are highly interested in the molecular mechanism, how retrograde signaling is activated by dysfunctional mitochondria. We will dissect the upstream signaling pathways by identifying the sensor kinases, responsible for the activation of the ISR pathway. By interference with genes involved in different stages of CL biosynthesis, we will create different CL pools and monitor ISR activation. In order to analyze the involvement of ROS in ISR activation, we will quench ROS in the BTHS mouse model by the expression of the plant alternative oxidase (AOX). We are interested in the molecular mechanism of the stabilization of the retrograde response transcription factor ATF5. ATF5 is imported into mitochondria and subsequently degraded in cells with unaffected mitochondria. Using an in vitro import assay, we will test the hypothesis that mitochondrial dysfunction induces a block of mitochondrial transport allowing ATF5 to stabilize and induce gene transcription in the nucleus.We will address the role of these pathways in metabolic remodeling in the heart. Fatty acids play a predominant role in supporting the energy demand in cardiac tissue. Our preliminary data show a significant reduction in -oxidation in BTHS mouse model and patient derived iPSC-CM. We will test the hypothesis that ISR signaling induces a remodeling of mitochondrial metabolism, thereby reducing fatty acid oxidation, which is particularly prone to ROS-generation. We also test the role of the mitochondrial LONP1 protease in inducing structural changes in the respiratory chain and exchanging regulatory subunits of the cytochrome c oxidase and other complexes of the respiratory chain. Respiratory chain remodeling and increased ROS production are common to many mitochondriopathies. Here we will shed light into a general mechanism how mitochondrial dysfunction is monitored by retrograde signaling and triggers an adaptive nuclear response.