Tafazzin Mutation Affecting Cardiolipin Leads to Increased Mitochondrial Superoxide Anions and Mitophagy Inhibition in Barth Syndrome

Abstract

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.

The lipid environment modulates cardiolipin and phospholipid constitution in wild type and tafazzin‐deficient cells

“…Indeed, abnormalities of PE and PC lipid species have been reported in heart and skeletal muscle of BTHS patients, 39 as well as a specific depletion of plasmenylcholines in the heart of Taz ‐deficient mice 40 and human lymphoblast cells 41 . On the other hand, the same PL classes were demonstrated to not be altered in tafazzin deficient cell culture 42 and drosophila 43 models.…”

Mechano‐energetic aspects of Barth syndrome

“…187,188 Interestingly, a particular defect in the processing of LC3 was recently identified in a cell model of Barth syndrome. 189 Consistent with this, studies in tafazzin deficient cell models have revealed defective biogenesis of mitophagosomes. 190…”

“…Also the adaptor molecule LC3 and functionally similar adaptor molecules, which label mitochondria for their degradation by mitophagy, have a high affinity for CL 187,188 . Interestingly, a particular defect in the processing of LC3 was recently identified in a cell model of Barth syndrome 189 . Consistent with this, studies in tafazzin deficient cell models have revealed defective biogenesis of mitophagosomes 190 …”

Studying Lipid-Related Pathophysiology Using the Yeast Model

“…The mitochondrial III 2 IV 2 supercomplex forms the terminal part of the electron transport chain and is essential for maintaining mitochondrial membrane potential and ATP synthesis (Schagger and Pfeiffer, 2000). In crd1Δ yeast, the III 2 IV 2 supercomplex is less stable than in wildtype cells, suggesting that CL is critical for mitochondrial homeostasis and bioenergetics (Pfeiffer et al, 2003;Mileykovskaya et al, 2005;Zhang et al, 2005;Claypool et al, 2008;Bottinger et al, 2012;Bazan et al, 2013;Peyta et al, 2016;Petit et al, 2020). A deficiency in CL remodeling is also associated with reduced bioenergetics (Brandner et al, 2005;Li et al, 2007).…”

“…BTHS patients relative to non-BTHS control cells. More recently, Petit et al (2020) showed that shRNA-mediated Taz knockdown in HeLa cells results in decreased ATP synthase activity and overall ATP level, with a concomitant decrease in maximal respiratory capacity and an increase in basal oxygen consumption. Similarly, Dudek et al (2013Dudek et al ( , 2016 showed reduced respiratory complex formation in cardiac tissue isolated from the BTHS mouse model and increased basal oxygen consumption coupled with decreased maximal respiratory capacity in induced pluripotent stem cells (iPSCs) derived from BTHS patients.…”