Spinocerebellar ataxias (SCAs) are a heterogenous group of neurodegenerative disorders which commonly inherited in an autosomal dominant manner. They cause muscle incoordination due to degeneration of the cerebellum and other parts of nervous system. Out of all the characterized (>50) SCAs, 14 SCAs are caused due to microsatellite repeat expansion mutations. Repeat expansions can result in toxic protein gain-of-function, protein loss-of-function, and/or RNA gain-of-function effects. The location and the nature of mutation modulate the underlying disease pathophysiology resulting in varying disease manifestations. Potential toxic effects of these mutations likely affect key major cellular processes such as transcriptional regulation, mitochondrial functioning, ion channel dysfunction and synaptic transmission. Involvement of several common pathways suggests interlinked function of genes implicated in the disease pathogenesis. A better understanding of the shared and distinct molecular pathogenic mechanisms in these diseases is required to develop targeted therapeutic tools and interventions for disease management. The prime focus of this review is to elaborate on how expanded 'CAG' repeats contribute to the common modes of neurotoxicity and their possible therapeutic targets in management of such devastating disorders.

Friedreich ataxia (FRDA) is an inherited disease that is typically caused by GAA repeat expansion within the first intron of the FXN gene coding for frataxin. This results in the frataxin deficiency that affects mostly muscle, nervous, and cardiovascular systems with progressive worsening of the symptoms over the years. This review summarizes recent progress that was achieved in understanding of molecular mechanism of the disease over the last few years and latest treatment strategies focused on overcoming the frataxin deficiency.

Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, is a human-adapted pathogen that does not productively infect other organisms. The ongoing relationship between N. gonorrhoeae and the human host is facilitated by the exchange of nutrient resources that allow for N. gonorrhoeae growth in the human genital tract. What N. gonorrhoeae 'eats' and the pathways used to consume these nutrients have been a topic of investigation over the last 50 years. More recent investigations are uncovering the impact of N. gonorrhoeae metabolism on infection and inflammatory responses, the environmental influences driving N. gonorrhoeae metabolism, and the metabolic adaptations enabling antimicrobial resistance. This mini-review is an introduction to the field of N. gonorrhoeae central carbon metabolism in the context of pathogenesis. It summarizes the foundational work used to characterize N. gonorrhoeae central metabolic pathways and the effects of these pathways on disease outcomes, and highlights some of the most recent advances and themes under current investigation. This review ends with a brief description of the current outlook and technologies under development to increase understanding of how the pathogenic potential of N. gonorrhoeae is enabled by metabolic adaptation.

Our knowledge on the asymmetric distribution of sphingomyelin (SM) in the plasma membrane is largely based on the biochemical analysis of erythrocytes using sphingomyelinase (SMase). However, recent studies showed that the product of SMase, ceramide, disturbs transmembrane lipid distribution. This led to the development of the complimentary histochemical method, which combines electron microscopy and SM-binding proteins. This review discusses the advantages and caveats of published methods of measuring transbilayer distribution of SM. Recent finding of the proteins involved in the transbilayer movement of SM will also be summarized.

Membrane asymmetry means that the two sides of membrane are structurally, physically and functionally different. Membrane asymmetry is largely related to the lipid sidedness and particularly to compositional (lipid head and acyl group) and physical (lipid packing order, charge, hydration and H-bonding interactions) differences in the inner and outer leaflets of lipid bilayer. Chemically, structurally and conformationally different non-covalent bound lipid molecules are physically fluid and deformable and enable to interact dynamically to form transient arrangements with asymmetry both perpendicular and parallel to the plane of the lipid bilayer. Although biological membranes are almost universally asymmetric however the asymmetry is not absolute since only drastic difference in the number of lipids per leaflet is found and symmetric arrangements are possible. Asymmetry is thought to direct and influence many core biological functions by altering the membrane's collective biochemical, biophysical and structural properties. Asymmetric transbilayer lipid distribution is found across all lipid classes, cells and near all endomembrane compartments. Why cell membranes are (a)symmetric and adopt almost exclusively highly entropically disfavored asymmetric state?

In mammalian cells, phospholipids are asymmetrically distributed between the outer and inner leaflets of the plasma membrane. The maintenance of asymmetric phospholipid distribution has been demonstrated to be required for a wide range of cellular functions including cell division, cell migration, and signal transduction. However, we recently reported that asymmetric phospholipid distribution is disrupted in Drosophila cell membranes, and this unique phospholipid distribution leads to the formation of highly deformable cell membranes. In addition, it has become clear that asymmetry in the trans-bilayer distribution of phospholipids is disturbed even in living mammalian cells under certain circumstances. In this article, we introduce our recent studies while focusing on the trans-bilayer distribution of phospholipids, and discuss the cellular functions of (a)symmetric biological membranes.

Many biological membranes present an asymmetric lipid distribution between the two leaflets that is known as the transbilayer lipid asymmetry. This asymmetry is essential for cell survival and its loss is related to apoptosis. In mammalian and yeast cells, ATP-dependent transport of lipids to the cytosolic side of the biological membranes, carried out by so-called lipid flippases, contributes to the transbilayer lipid asymmetry. Most of these lipid flippases belong to the P4-ATPase protein family, which is also present in plants. In this review, we summarize the relatively scarce literature concerning the presence of transbilayer lipid asymmetry in different plant cell membranes and revise the potential role of lipid flippases of the P4-ATPase family in generation and/or maintenance of this asymmetry.

The development of electron cryomicroscopy (cryo-EM) has evolved immensely in the last several decades and is now well-established in the analysis of protein structure both in isolation and in their cellular context. This review focuses on the history and application of cryo-EM to the analysis of membrane architecture. Parallels between the levels of organization of protein structure are useful in organizing the discussion of the unique parameters that influence membrane structure and function. Importantly, the timescales of lipid motion in bilayers with respect to the timescales of sample vitrification is discussed and reveals what types of membrane structure can be reliably extracted in cryo-EM images of vitrified samples. Appreciating these limitations, a review of the application of cryo-EM to examine the lateral organization of ordered and disordered domains in reconstituted and biologically derived membranes is provided. Finally, a brief outlook for further development and application of cryo-EM to the analysis of membrane architecture is provided.

Biomembranes are fundamental to our understanding of the cell, the basic building block of all life. An intriguing aspect of membranes is their ability to assume a variety of shapes, which is crucial for cell function. Here, we review various membrane shaping mechanisms with special focus on the current understanding of how local curvature and local rigidity induced by membrane proteins leads to emerging forces and consequently large-scale membrane deformations. We also argue that describing the interaction of rigid proteins with membranes purely in terms of local membrane curvature is incomplete and that changes in the membrane rigidity moduli must also be considered.

Eukaryotic pathogens with an intracellular parasitic lifestyle are shielded from extracellular threats during replication and growth. In addition to many nutrients, parasites scavenge host cell lipids to establish complex membrane structures inside their host cells. To counteract the disturbance of the host cell plasma membrane they have evolved strategies to regulate phospholipid asymmetry. In this review, the function and importance of lipid asymmetry in the interactions of intracellular protozoan parasites with the target and immune cells of the host are highlighted. The malaria parasite Plasmodium infects red blood cells and extensively refurbishes these terminally differentiated cells. Cholesterol depletion and an altered intracellular calcium ion homeostasis can lead to disruption in erythrocyte membrane asymmetry and increased exposure of phosphatidylserine (PS). Binding to the PS receptor on monocytes and macrophages results in phagocytosis and destruction of infected erythrocytes. Leishmania parasites display apoptotic mimicry by actively enhancing PS exposure on their surface to trigger increased infection of macrophages. In extracellular Toxoplasma gondii a P4-type ATPase/CDC50 co-chaperone pair functions as a flippase important for exocytosis of specialised secretory organelles. Identification and functional analysis of parasite lipid-translocating proteins, i.e. flippases, floppases, and scramblases, will be central for the recognition of the molecular mechanisms of parasite/host interactions. Ultimately, a better understanding of parasitic diseases, host immunity, and immune escape by parasites require more research on the dynamics of phospholipid bilayers of parasites and the infected host cell.

The distinctive feature of Gram-negative bacteria is the presence of an asymmetric outer membrane (OM), which acts as a permeation barrier blocking the diffusion of noxious components such as antibiotics that could compromise cell survival. The outer membrane has an inner leaflet, mainly formed by phospholipids (PLs), and the outer leaflet, composed of molecules of lipopolysaccharide (LPS). Building this membrane is a very complex process as every OM element needs to be transported from the cytoplasm or the inner membrane and properly placed in the OM. In addition, the asymmetry needs to be maintained to guarantee the barrier function of the membrane. The presence of misplaced PLs in the outer leaflet of the OM causes increased permeability, endangering cell survival. The Mla system (maintenance of OM lipid asymmetry) has been linked to the removal of the misplaced PLs, restoring OM asymmetry. The Mla system has elements in all compartments of the cell envelope: the lipoprotein MlaA in complex with the trimeric porins OmpC/F in the OM, MlaC in the periplasmic space and an ABC transporter in the inner membrane called MlaFEDB. While genetic and structural work suggest that the Mla pathway is retrograde (PL movement from OM to IM), several groups have advocated that transport could happen in an anterograde fashion (from IM to OM). However, recent biochemical studies strongly support retrograde transport. This review provides an overview of the current knowledge of the Mla system from a structural point of view and addresses the latest biochemical findings and their impact in transport directionality.

Cell membranes are quasi-bidimensional soft systems formed by multipoles in an ordered array that can be polarized in an electric field. Consequently, electrostatic potentials emerge inside membranes, and membranes respond to external electric fields. From a mechanical perspective, membranes can be easily compressed-expanded, laterally deformed, and curved. Bending is particularly easy, and this kind of deformation translates to changes in the relative positions of the negative and positive charges, leading to strain gradient-induced polarization. Conversely, an external electric field gradient will exert a bending stress that translates to mechanical membrane deformation. These phenomena are described through membrane flexoelectricity. Here, we describe this property in lipid bilayers and cell membranes and summarize the studies in the field with emphasis on the effects promoted by membrane asymmetry.

Many cellular lipid bilayers consist of leaflets that differ in their lipid composition - a non-equilibrium state actively maintained by cellular sorting processes that counter passive lipid flip-flop. While this lipidomic aspect of membrane asymmetry has been known for half a century, its elastic and thermodynamic ramifications have garnered attention only fairly recently. Notably, the torque arising when lipids of different spontaneous curvature reside in the two leaflets can be counterbalanced by a difference in lateral mechanical stress between them. Such membranes can be essentially flat in their relaxed state, despite being compositionally strongly asymmetric, but they harbor a surprisingly large but macroscopically invisible differential stress. This hidden stress can affect a wide range of other membrane properties, such as the resistance to bending, the nature of phase transitions in its leaflets, and the distribution of flippable species, most notably sterols. In this short note we offer a concise overview of our recently proposed basic framework for capturing the interplay between curvature, lateral stress, leaflet phase behavior, and cholesterol distribution in generally asymmetric membranes, and how its implied signatures might be used to learn more about the hidden but physically consequential differential stress.

A key feature of eukaryotic cells is the asymmetric distribution of lipids along their secretory pathway. Because of the biological significance of these asymmetries, it is crucial to define the mechanisms which create them. Extensive studies have led to the identification of lipid transfer proteins (LTPs) that work with lipid-synthesizing enzymes to carry lipids between two distinct membranes in a directional manner, and are thus able to create asymmetries in lipid distribution throughout the cell. These networks are often in contact sites where two organelle membranes are in close proximity for reasons we have only recently started to understand. A question is whether these networks transfer lipids en masse within the cells or adjust the lipid composition of organelle membranes. Finally, recent data have confirmed that some networks organized around LTPs do not generate lipid asymmetries between membranes but sense them and rectify the lipid content of the cell.

The complex two-membrane organization of the envelope of Gram-negative bacteria imposes an unique biosynthetic and topological constraints that can affect translocation of lipids and proteins synthesized on the cytoplasm facing leaflet of the cytoplasmic (inner) membrane (IM), across the IM and between the IM and outer membrane (OM). Balanced growth of two membranes and continuous loss of phospholipids in the periplasmic leaflet of the IM as metabolic precursors for envelope components and for translocation to the OM requires a constant supply of phospholipids in the IM cytosolic leaflet. At present we have no explanation as to why the biogenic E. coli IM displays asymmetry. Lipid asymmetry is largely related to highly entropically disfavored, unequal headgroup and acyl group asymmetries which are usually actively maintained by active mechanisms. However, these mechanisms are largely unknown for bacteria. Alternatively, lipid asymmetry in biogenic IM could be metabolically controlled in order to maintain uniform bilayer growth and asymmetric transmembrane arrangement by balancing temporally the net rates of synthesis and flip-flop, inter IM and OM bidirectional flows and bilayer chemical and physical properties as spontaneous response. Does such flippase-less or 'lipid only", 'passive' mechanism of generation and maintenance of lipid asymmetry exists in the IM? The driving force for IM asymmetry can arise from the packing requirements imposed upon the bilayer system during cell division through disproportional distribution of two negatively curved phospholipids, phosphatidylethanolamine and cardiolipin, with consistent reciprocal tendency to increase and decrease lipid order in each membrane leaflet respectively.

Short-chain fatty acids are known modulators of host-microbe interactions and can affect human health, inflammation, and outcomes of microbial infections. Acetate is the most abundant but least well-studied of these modulators, with most studies focusing on propionate and butyrate, which are considered to be more potent. In this mini-review, we summarize current knowledge of acetate as an important anti-inflammatory modulator of interactions between hosts and microorganisms. This includes a summary of the pathways by which acetate is metabolized by bacteria and human cells, the functions of acetate in bacterial cells, and the impact that microbially derived acetate has on human immune function.

The human genome contains numerous genetic polymorphisms contributing to different health and disease outcomes. Tandem repeat (TR) loci are highly polymorphic yet under-investigated in large genomic studies, which has prompted research efforts to identify novel variations and gain a deeper understanding of their role in human biology and disease outcomes. We summarize the current understanding of TRs and their implications for human health and disease, including an overview of the challenges encountered when conducting TR analyses and potential solutions to overcome these challenges. By shedding light on these issues, this article aims to contribute to a better understanding of the impact of TRs on the development of new disease treatments.