sirolimus and Barth-Syndrome

Topics: Animals; Autophagy; Barth Syndrome; Cardiolipins; Cardiomyopathies; Cardiomyopathy, Dilated; Fibroblasts; Mechanistic Target of Rapamycin Complex 1; Mice; Mitophagy; Sirolimus; Ubiquitin-Protein Ligases

Tafazzin is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of the tafazzin gene cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. We again highlight the fact that the tafazzin deficiency is also linked to defective oxidative phosphorylation associated with oxidative stress. All the mitochondrial events are positioned in a context where mitophagy is a key element in mitochondrial quality control. Here, we investigated the role of tafazzin in mitochondrial homeostasis dysregulation and mitophagy alteration. Using a HeLa cell model of tafazzin deficiency, we show that dysregulation of tafazzin in HeLa cells induces alteration of mitophagy. Our findings provide some additional insights into mitochondrial dysfunction associated with Barth syndrome, but also show that mitophagy inhibition is concomitant with apoptosis dysfunction through the inability of abnormal mitochondrial cardiolipin to assume its role in cytoplasmic signal transduction. Our work raises hope that pharmacological manipulation of the mitophagic pathway together with mitochondrially targeted antioxidants may provide new insights leading to promising treatment for these highly lethal conditions.

Topics: Acyltransferases; Adenylate Kinase; Apoptosis; Autophagy; Barth Syndrome; Cardiolipins; Cell Adhesion; Cell Membrane Permeability; Cell Proliferation; Energy Metabolism; HeLa Cells; Humans; Microtubule-Associated Proteins; Mitochondria; Mitophagy; Mutation; Organelle Biogenesis; Sirolimus; Superoxides; Transcription Factors