Browsing by Subject "Cardiolipin"

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    Regulation of Bacterial Two-Component Systems by Cardiolipin
    (American Society for Microbiology, 2023) Yeo, Won-Sik; Dyzenhaus, Sophie; Torres, Victor J.; Brinsmade, Shaun R.; Bae, Taeok; Microbiology and Immunology, School of Medicine
    The regulation of membrane protein activity for cellular functions is critically dependent on the composition of phospholipid membranes. Cardiolipin, a unique phospholipid found in bacterial membranes and mitochondrial membranes of eukaryotes, plays a crucial role in stabilizing membrane proteins and maintaining their function. In the human pathogen Staphylococcus aureus, the SaeRS two-component system (TCS) controls the expression of key virulence factors essential for the bacterium’s virulence. The SaeS sensor kinase activates the SaeR response regulator via phosphoryl transfer to bind its gene target promoters. In this study, we report that cardiolipin is critical for sustaining the full activity of SaeRS and other TCSs in S. aureus. The sensor kinase protein SaeS binds directly to cardiolipin and phosphatidylglycerol, enabling SaeS activity. Elimination of cardiolipin from the membrane reduces SaeS kinase activity, indicating that bacterial cardiolipin is necessary for modulating the kinase activities of SaeS and other sensor kinases during infection. Moreover, the deletion of cardiolipin synthase genes cls1 and cls2 leads to reduced cytotoxicity to human neutrophils and lower virulence in a mouse model of infection. These findings suggest a model where cardiolipin modulates the kinase activity of SaeS and other sensor kinases after infection to adapt to the hostile environment of the host and expand our knowledge of how phospholipids contribute to membrane protein function.
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    What can ATP content tell us about Barth syndrome muscle phenotypes?
    (OAE, 2025) Brault, Jeffrey J.; Conway, Simon J.; Anatomy, Cell Biology and Physiology, School of Medicine
    Adenosine triphosphate (ATP) is the energy currency within all living cells and is involved in many vital biochemical reactions, including cell viability, metabolic status, cell death, intracellular signaling, DNA and RNA synthesis, purinergic signaling, synaptic signaling, active transport, and muscle contraction. Consequently, altered ATP production is frequently viewed as a contributor to both disease pathogenesis and subsequent progression of organ failure. Barth syndrome (BTHS) is an X-linked mitochondrial disease characterized by fatigue, skeletal muscle weakness, cardiomyopathy, neutropenia, and growth delay due to inherited TAFAZZIN enzyme mutations. BTHS is widely hypothesized in the literature to be a model of defective mitochondrial ATP production leading to energy deficits. Prior patient data have linked both impaired ATP production and reduced phosphocreatine to ATP ratios (PCr/ATP) in BTHS children and adult hearts and muscles, suggesting a primary role for perturbed energetics. Moreover, although only limited direct measurements of ATP content and ADP/ATP ratio (an indicator of the energy available from ATP hydrolysis) have so far been carried out, analysis of divergent BTHS animal models, cultured cell types, and diverse organs has failed to uncover a unifying understanding of the molecular mechanisms linking TAFAZZIN deficiency to perturbed muscle energetics. This review mainly focuses on the energetics of striated muscle in BTHS mitochondriopathy.