Pathophysiologic implications of membrane phospholipid asymmetry in blood cells

Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
Blood (Impact Factor: 10.43). 03/1997; 89(4):1121-32.
Source: PubMed
Download full-text


Available from: R.F.A. Zwaal, Jul 06, 2015
  • Source
    [Show description] [Hide description]
    DESCRIPTION: Patients with the rare, X-linked, mitochondrial disorder Barth syndrome (BTHS) suffer from moderate to severe neutropenia amongst other symptoms. BTHS is caused by mutations in the TAZ gene, encoding tafazzin, which is involved in cardiolipin metabolism, a phospholipid restricted to the mitochondrial inner membrane. It has previously been reported that neutrophils from BTHS patients avidly bind annexin V, indicative of phosphatidyl serine (PS) exposure -a well-described ‘eat me’ signal for apoptotic cells- in the absence of apoptosis. PS exposure is normally actively prevented by a fast acting lipid transporter called flippase. In this study, we addressed the question why only neutrophils, and not other immune cells, are affected in BTHS patients. We found that ATP levels in BTHS neutrophils were normal even though their mitochondria were consistently defective. In addition, we demonstrate a linear inverse correlation between the absolute neutrophil cell count in BTHS patients and their level of annexin-V binding. Finally, we uncover a potential link between reduced mitochondrial membrane potential observed in BTHS cells and flippase inhibition by Ca2+ in neutrophils, leading to PS exposure. We hypothesize that this mechanism may be responsible for increased neutrophil clearance and neutropenia observed in BTHS patients.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The plasma membrane, trans-Golgi network and endosomal system of eukaryotic cells are populated with flippases that hydrolyze ATP to help establish asymmetric phospholipid distributions across the bilayer. Upholding phospholipid asymmetry is vital to a host of cellular processes, including membrane homeostasis, vesicle biogenesis, cell signaling, morphogenesis and migration. Consequently, defining the identity of flippases and their biological impact has been the subject of intense investigations. Recent work has revealed a remarkable degree of kinship between flippases and cation pumps. In this Commentary, we review emerging insights into how flippases work, how their activity is controlled according to cellular demands, and how disrupting flippase activity causes system failure of membrane function, culminating in membrane trafficking defects, aberrant signaling and disease. © 2015. Published by The Company of Biologists Ltd.
    Journal of Cell Science 04/2015; 128(11). DOI:10.1242/jcs.102715 · 5.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs-or specific EV cargoes-are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases.
    Biogerontology 06/2014; 16(2). DOI:10.1007/s10522-014-9510-7 · 3.01 Impact Factor