Simpson, P. J. | bioRxiv Science

bioRxiv2025

Integrated Multi-Omics Mapping of Mitochondrial Dysfunction and Substrate Preference in Barth Syndrome Cardiac Tissue

Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. With this study describe a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.

molecular biology↗

bioRxiv2020

Myosin XI drives polarized growth by vesicle clustering and local enrichment of F-actin in Physcomitrium (Physcomitrella) patens

In tip-growing plant cells, growth results from myosin XI and F-actin mediated deposition of cell wall polysaccharides contained in secretory vesicles. Previous evidence showed that myosin XI anticipates F-actin accumulation at the cells tip, suggesting a mechanism where vesicle clustering via myosin XI promotes F-actin polymerization. To evaluate this model, we used a conditional loss-of-function strategy by generating Physcomitrium (Physcomitrella) patens plants harboring a myosin XI temperature-sensitive allele. We found that loss of myosin XI function alters tip cell morphology, vacuolar homeostasis, and cell viability, but not following F-actin depolymerization. Importantly, our conditional loss-of-function analysis shows that myosin XI clusters and directs vesicles at the tip of the cell, which induces F-actin polymerization, increasing F-actins local concentration. Our findings support the role of myosin XI in vesicle clustering and F-actin organization, necessary for tip growth, and deepen our understanding of additional myosin XI functions.

cell biology↗