Biology subjects

Wohlfarter, Y.

Publications and source records attributed to Wohlfarter, Y..

4 recordsLinked to original sources

bioRxiv2025

Disturbed mitochondrial maturation in cardiolipin remodeling-deficient cardiomyocytes

Barth syndrome, a rare X-linked genetic disorder, features early-onset cardiomyopathy. The causal gene, TAFAZZIN, encodes a transacylase that mediates acyl chain remodeling of cardiolipin, a critical phospholipid in the inner mitochondrial membrane. While Barth syndrome exhibits hallmark cardiolipin abnormalities, the precise mechanisms linking TAFAZZIN deficiency and disturbed cardiolipin metabolism to progressive cardiac dysfunction remain unclear. In this study, we modeled Barth syndrome cardiomyopathy in human induced pluripotent stem cell-derived cardiomyocytes with in vitro maturation treatments that simulate heart developmental stimuli. We found that cardiomyocyte maturation involves progressive cristae dynamics associated with protein and lipid alterations in the inner mitochondrial membrane. TAFAZZIN-deficient cardiomyocytes fail to adapt to the developmental stimuli, resulting in damaged cristae, compromised mitochondrial respiration, and cardiomyocyte dysfunction. These results demonstrate that TAFAZZIN deficiency perturbs functional and structural development of mitochondria, which may contribute to mitochondrial dysfunction and associated childhood progression to cardiomyopathy in Barth syndrome.

developmental biology↗

bioRxiv2024

Mitochondrial cardiolipin metabolism controlled by tafazzin enables ferroptosis

Mitochondria are important producers of reactive oxygen species, which are involved in triggering ferroptosis, a lipid peroxidation driven form of cell death. Paradoxically, in the rare inherited metabolic disease Barth Syndrome, we discovered a protection from erastin-induced ferroptosis, despite intrinsically elevated mitochondrial ROS levels. The affected transacylase tafazzin, which is mutated in Barth Syndrome, is pivotal for remodeling of the dimeric phospholipid cardiolipin. They unique to mitochondria and essential for shaping their membrane functionalities. We investigated which downstream effects of the pathogenic membrane alterations are responsible for the protective effect against ferroptosis. We found that while iron metabolism, the unsaturation of membrane lipids, and the metabolic activity of the cells were modifying factors, they were not causal. However, we observed that cardiolipin abnormalities are not limited to impair only inner, but also outer mitochondrial membrane protein complexes. Specifically, they impact abundance and oligomerization of voltage-dependent anion channels (VDAC) in response to oxidative stress. We found that tafazzin deficiency via alteration of cardiolipins affects VDAC functionality, thereby modulating small molecule transport and signaling between mitochondria and the remaining cell. This is in line with a reduction of mitochondria-associated membranes (MAM) sites that are formed through VDACs and trapping ROS in mitochondria where they are unable to contribute to ferroptosis. These findings demonstrate that the mitochondrial membrane architecture impacting on subcellular small molecule distribution crucially impact on the manifestation of cell fate decisions, including ferroptosis.

molecular biology↗

bioRxiv2024

Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth Syndrome

Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ- KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.

cell biology↗

bioRxiv2020

Unequivocal mapping of molecular ether lipid species by LC-MS/MS in plasmalogen-deficient mice

Deficient ether lipid biosynthesis in rhizomelic chondrodysplasia punctata and other disorders is associated with a wide range of severe symptoms including small stature with proximal shortening of the limbs, contractures, facial dysmorphism, congenital cataracts, ichthyosis, spasticity, microcephaly, and mental disability. Mouse models are available but show less severe symptoms. In both humans and mice it has remained elusive which of the symptoms can be attributed to lack of plasmanyl or plasmenyl ether lipids. The latter compounds, better known as plasmalogens, harbor a vinyl ether double bond conferring special chemical and physical properties. Discrimination between plasmanyl and plasmenyl ether lipids is a major analytical challenge, especially in complex lipid extracts with many isobaric species. Consequently, these lipids are often neglected also in recent lipidomic studies. Here we present a comprehensive LC-MS/MS based approach that allows unequivocal distinction of these two lipid subclasses based on their chromatographic properties. The method was validated using a novel plasmalogen-deficient mouse model which lacks plasmanylethanolamine desaturase and therefore cannot form plasmenyl ether lipids. We demonstrate that plasmanylethanolamine desaturase deficiency causes an accumulation of plasmanyl species, a little studied but biologically important substance class.

biochemistry↗