The asymmetric distribution of phospholipids between membrane leaflets is a hallmark of all known cells, yet many fundamental questions about membrane lipid asymmetry remain unanswered. Why do cells invest energy to establish and maintain this thermodynamically unstable state? How do cells exploit lipid asymmetry to support essential functions? What are the consequences for health and disease when this organization breaks down? Recent identification of bona fide lipid scramblases, which catalyze rapid phospholipid translocation across the hydrophobic membrane core (lipid flip-flop), has shed new light on these longstanding questions. In particular, studies of the Ca²⁺-activated phospholipid scramblase TMEM16F have revealed how regulated lipid scrambling can couple Ca²⁺ signaling to membrane remodeling, phosphatidylserine (PS) exposure, cellular communication, and disease pathogenesis. In this review, we examine the biology of regulated transmembrane phospholipid flip-flop mediated by lipid scramblases, using TMEM16F as a prototypical model to illustrate core molecular mechanisms, physiological functions, pathological implications, and emerging pharmacological opportunities. By placing TMEM16F within the broader landscape of lipid scramblases and scramblase-like proteins, we highlight how regulated membrane lipid scrambling shapes cell physiology and disease. We also discuss critical knowledge gaps and future directions for understanding this rapidly evolving field.
The chronic hypoxia experienced by high-altitude residents profoundly impacts pregnancy, influencing maternal health, placental function, and the growth and development of the fetus. Exposure to chronic hypoxia during pregnancy increases the risk of complications like preeclampsia and fetal growth restriction and has lasting effects on offspring, extending from infancy to adulthood. Understanding how chronic hypoxia alters physiological adaptations to pregnancy and pregnancy outcomes is essential for high-altitude populations and for gaining broader insights into the mechanisms underlying reduced fetoplacental oxygenation in complicated pregnancy at sea level. This review summarizes current knowledge on physiological adaptations during pregnancy under hypoxic conditions. We describe key studies on the effects of high altitude and chronic hypoxia on pregnancy and examine the maternal, placental, fetal, and long-term physiological consequences. Finally, we review preclinical and clinical studies aimed at identifying interventions that could prevent or alleviate the adverse effects of chronic hypoxia on pregnancy outcomes and beyond.
Extracellular vesicles (EVs) are lipid-bound nanostructures that play important roles in reproduction as universal mediators of bidirectional cell-to-cell communication. EVs transfer diverse cargoes between reproductive cells, influencing fundamental reproductive processes such as gametogenesis and pregnancy. In the male reproductive tract, specialized EVs such as epididymosomes and prostasomes regulate sperm activation, motility, and capacitation, exerting some of these effects within the female reproductive tract as well. In the female reproductive tract, EVs found in follicular fluid, oviduct, and uterus aid in oocyte maturation, fertilization, and the vital embryo development and embryo-maternal crosstalk necessary for successful implantation, including after in vitro fertilization. With advancing gestation, EVs continue to play crucial roles in mediating communication between maternal, placental and fetal compartments with the ultimate aim of promoting immunotolerance and development of the allogeneic fetus. Focusing on the human reproductive system, development of obstetric conditions such as preeclampsia and gestational diabetes is marked by a significant increase in EV release and systemic impacts, including endothelial dysregulation, perturbation of metabolic homeostasis and disruption to the blood-brain barrier. Disruption of EV-mediated signaling is linked to reproductive pathologies, but detailed etiologies are not yet defined. Importantly, EVs offer an exciting avenue for both biomarker discovery and therapeutic applications. Our advancing understanding of how EVs deliver their molecular cargo and influence gene expression in recipient cells holds promise for manipulating these processes and improving the diagnosis and treatment of infertility and pregnancy complications.
Manganese (Mn) is an essential metal required for many physiological functions, and deficiency or overexposure is associated with neurological dysfunction and neuropathology. Tight homeostatic control of Mn in the body is required to maintain optimal physiological levels and protect against toxicity. Mn homeostasis has been studied for decades, but there has been limited knowledge of the molecular mechanisms until recently, when the first human genetic disorders of Mn metabolism were described. These discoveries led to the identification of the Mn transporters SLC30A10, SLC39A14, and SLC39A8, which spurred a transformation of research into Mn homeostatic mechanisms. This review provides an overview of Mn physiology and homeostasis and the role of the critical Mn transporters and discusses the progress made within recent years toward understanding how these transporters work together to regulate brain Mn biology under both physiological and pathophysiological Mn conditions.
One of the most remarkable properties of the mammalian brain is its ability to change in response to experience, a phenomenon referred to as neural plasticity. Synaptic plasticity specifically refers to activity-dependent changes in synaptic strength or efficacy of synaptic transmission. Synaptic plasticity enables us to acquire and perform different sensory, motor, and cognitive tasks, such as playing a musical instrument or learning a language. Synaptic plasticity is involved in the creation of memories and is a phenomenon that varies and evolves over an individual's lifetime. The most extensively studied forms of synaptic plasticity in the mammalian brain are long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. Sixty years ago, an abstract by Terje Lømo first described a long-lasting synaptic potentiation induced by high-frequency afferent stimulation (Lømo T. Acta Physiol Scand 68: 128, 1966), and 7 years later the first full paper on LTP was published by Tim Bliss and Terje Lømo in the Journal of Physiology (Bliss TV, Lomo T. J Physiol 232: 331-356, 1973). Since then, "neuroplasticity" or "brain plasticity" has emerged as a central theme of research in neuroscience. Increasing evidence supports the supposition that LTP is a natural phenomenon that is directly involved in neurodevelopment and learning and memory processes. Additionally, different brain disorders seem to be due to alterations in brain plasticity. Since its discovery, thousands of papers have appeared describing the underlying mechanisms and demonstrating that LTP is a robust and general brain mechanism that exists in vivo in animals including humans. Currently, the field is dedicated to defining more precisely the functions in which LTP (and LTD) is involved, including development, learning, and memory, as well as their roles in brain disorders. Here, we describe the present state of the field. We foresee that important discoveries remain to be made with implications for the understanding of, and treatment of, brain disorders.
