Plasma membrane integrity: implications for health and disease

Abstract

Plasma membrane integrity is essential for cellular homeostasis. In vivo, cells experience plasma membrane damage from a multitude of stressors in the extra- and intra-cellular environment. To avoid lethal consequences, cells are equipped with repair pathways to restore membrane integrity. Here, we assess plasma membrane damage and repair from a whole-body perspective. We highlight the role of tissue-specific stressors in health and disease and examine membrane repair pathways across diverse cell types. Furthermore, we outline the impact of genetic and environmental factors on plasma membrane integrity and how these contribute to disease pathogenesis in different tissues.

Keywords: Cell biology; Disease; Lipid peroxidation; Membrane damage; Membrane repair; Plasma membrane; Pore formation; Tissue injury; Vesicle trafficking.

Fig. 1

Plasma membrane damage is comprised of chemical disruptions and physical breaches. a Chemical disruptions of the plasma membrane can alter its biophysical properties and lead to a breach. Oxidative stress and intracellular iron promote lipid peroxidation of poly-unsaturated fatty acids leading to the removal of damaged fragments and destabilization of the plasma membrane. Membrane lipids are subject to enzymatic damage by host or foreign phospholipases. Alterations in membrane fluidity through interactions with amphipathic molecules or cholesterol extraction can weaken membrane resistance upon subsequent insult. b Depending on size and frequency, physical breaches elicit lytic or non-lytic damage and require active repair to restore membrane integrity. Nanoruptures result in ion imbalances and the leakage of small molecules, whereas membrane tears result in extensive leakage of cytosolic cargo. Larger membrane tears (> 100 nm) are broadly distinguished based on different repair requirements. Upon recognition of unique host receptors, pore-forming proteins can assemble into transmembrane pores that differ in terms of size, structure, and ion flux

Fig. 2

Five major sources of plasma membrane damage. These sources of damage can be highly overlapping as one type of membrane injury can lead to another. (a) Cells experience mechanical stress from physiological events (e.g., locomotion), cell migration, and through interactions with inert substances in the local environment, all of which elicit membrane damage in the form of nanoruptures and tears. (b) Reactive oxygen species present in the extracellular environment or those generated from irradiation can promote lipid peroxidation. Additional sources of chemical disruptions include amphipathic molecules (e.g., NSAIDs and alcohol), which can compromise membrane integrity either through direct interactions or indirectly via oxidative stress. (c) Microbial species employ several strategies to induce plasma membrane damage. Virulence factors can inflict chemical disruptions (e.g., phospholipases) and physical breaches (e.g., pore-forming toxins); meanwhile, larger species can also exert brute force to damage host plasma membrane. (d) Immune cells elicit membrane damage, namely through pore-forming proteins and antimicrobials, under several unique contexts such as immune surveillance and neutrophil extracellular traps. (e) Intracellular sources of plasma membrane damage include oxidative stress, which can entice lipid peroxidation, and the leakage of cytotoxic enzymes from lysosomes. In the context of cell death, many pathways employ pore-induced damage (e.g., necroptosis, secondary necrosis, pyroptosis) whereas others are characterized by chemical disruptions (e.g., ferroptosis)

Fig. 3

Plasma membrane repair pathways to seal a physical breach. Depending on the extent of damage, several different pathways can cooperatively facilitate wound closure. (a) Exocytosis can relieve membrane tension at the wound site to promote wound closure. Vesicle recruitment to the cell surface occurs through kinesin- and myosin-dependent transport and may require additional support by proteins such as MG53. At the wound site, calcium-dependent fusion machinery such as synaptotagmins (SYT) or dysferlin (DYSF) mediate vesicle fusion. (b) Patching entails inter-vesicle fusion underneath the wound site to generate a membrane patch to seal large tears. (c) Lysosomal exocytosis can promote caveolar endocytosis upon the extracellular release of cathepsins and acid sphingomyelinase (ASM). The fate of endocytosed lesions is determined upon sorting in multivesicular bodies. (d) Concentric zones of actin regulators (e.g., RHOA, myosin-II, CDC42) can form around the wound site to facilitate closure by actomyosin contractions. (e) The accumulation of vesicles, calcium-sensitive proteins (e.g., ANXA1), and mitochondria at the wound site can form a temporary plug to limit diffusion of materials between the extra- and intra-cellular environment. (f) Different annexins can assemble along the wound edge to limit wound expansion (ANXA5), induce membrane curvature (ANXA4), and generate constriction force (ANXA6) to seal a breach. (g) The ANXA7-dependent recruitment of ESCRT-III machinery to the wound site can lead to membrane scission and the release of damaged membrane

Fig. 4

Plasma membrane damage and repair in the lung, gastrointestinal tract, skin, vasculature, and bone. Red arrows: sources of plasma membrane damage; black arrows: repair pathways; gray arrows: forms of cellular resistance. Human body was created with BioRender.com. (i) Pneumocytes: Mechanical stress during ventilation is typically alleviated by surfactant. Damage-induced ATP leakage promotes lysosomal exocytosis via P2Y2 receptors. MG53 facilitates repair in type I cells through caveolar endocytosis, although its protective role in type II cells remains unclear. Type II cells likely facilitate resealing through ANXA7-dependent fusion of surfactant granules. During S. aureus infection, pneumocytes evade damage from pore-forming toxin by releasing decoy exosomes enriched in host receptor ADAM10. (ii) Gastric Epithelium: Mucus integrity is compromised during H. pylori infection and by amphiphilic molecules such as NSAIDs and alcohol. Pore formation by VacA disrupts microvilli organization upon CAPN1-mediated cleavage of ezrin. Cholesterol extraction and lipid peroxidation are achieved by virulence factors including cholesterol-α-glucoside transferase (CGT), γ-glutamyl transpeptidase (GGT), and urease (via monochloramine, NH4Cl). Gastric repair includes lysosomal exocytosis and annexins, whereas HSP70 activity alleviates chemical disruptions although its exact role remains unclear. Meanwhile, NSAIDs and alcohol elicit damage through direct interactions with plasma membrane phospholipids or indirectly via oxidative stress. Cytoprotective factors include calpains and prostaglandin E2 (PGE2), the latter of which stimulates bicarbonate (HCO3-) release via SLC26A9 to alleviate acid-induced injury. (iii) Intestinal Epithelium: Enterocytes rid bacterial pore-forming toxins (~ 1–2 nm) through cytoplasm extrusion, preceded by oxidative stress as evident by lipid droplet formation and mitochondrial damage. Pores are also removed through vesicle trafficking events and microvilli shedding. Dietary lectins can lead to microvilli abnormalities and inhibit mucus secretion in goblet cells which is a form of membrane resealing. Other dietary molecules, such as poly-unsaturated fatty acids (PUFA) and undigested gliadin peptide, can promote damage through lipid peroxidation and pyroptosis, respectively. (iv) Keratinocytes: During S. aureus infection, keratinocytes internalize α-toxin pores and release them via exosomes. Resistance is achieved through the filaggrin (FLG)-dependent release of acid sphingomyelinase to reduce the availability of exofacial sphingomyelin, an alternative receptor of α-toxin. Ultraviolet A irradiation causes lipid peroxidation that is alleviated by NRF2-dependent antioxidant defenses. Phospholipase D (PLD) activity promotes vesicle fusion events such as lysosomal exocytosis. Alongside repair, caveolar endocytosis can result in caspase-8-mediated apoptosis. (v) Endothelium: Endothelial cells buffer hemodynamic force through caveolae. Advanced glycation end products (AGEs) entice lipid peroxidation whereas overexpression of receptor for AGEs (RAGE) prevents F-actin remodeling required for resealing. Complement-induced damage triggers the release of von Willebrand factor (VWF) which can limit further complement deposition. (vi) Osteoblasts, Osteocytes: Bone cells experience nanoruptures during locomotion that can be repaired through exocytosis with an apparent role for dietary Vitamin E in limiting further oxidative damage. ATP leakage from the wound site initiates calcium-dependent mechanotransduction in nearby, uninjured cells through P2 receptors

Fig. 5

Plasma membrane damage and repair in the liver, pancreas, nervous system, kidney, and muscle. Red arrows: sources of plasma membrane damage; black arrows: repair pathways; gray arrows: forms of cellular resistance. Human body was created with BioRender.com. (i) Hepatocytes: Alcohol and drug metabolism or the accumulation of lipids and bile acids can promote lipid peroxidation which is alleviated by glutathione peroxidase 4 (GPX4) activity. Basolateral wounds can be removed through membrane scission whereas apical protrusions are prone to rupture. Biliary phospholipids confer protection by reducing the ability of bile acids to solubilize membrane. Ischemic-reperfusion injury (I/R injury) triggers dysferlin-mediated exocytosis which may involve ANXA6 activity given its role in hepatocyte vesicle trafficking. (ii) Pancreatic Cells: Acinar cell damage can indirectly arise following exposure to stressors such as alcohol, drugs, and bile. Abnormally high levels of intracellular calcium prompt the fusion of zymogen granules (ZG) with lysosomes (L), leading to the premature activation of zymogens (e.g., trypsin) which inflict membrane damage upon leakage into the cytosol. Pancreatic β cells experience membrane damage from amylin aggregates in the extracellular environment that are typically prevented by insulin co-secretion. In both cell types, repair likely involves exocytosis based on the abundance of granules and lysosomes underlying the plasma membrane. (iii) Neurons: Neuronal membrane damage can arise from exposure to protein aggregates (e.g., β-amyloid) in the extra- or intra-cellular environment which elicit mechanical damage and oxidative stress. Depending on the protein, resistance against intracellular aggregation may be achieved through multivesicular body sorting and lysosomal degradation or exocytosis. Lesions from β-amyloid aggregates may be removed through caveolar endocytosis and ESCRT-III activity as observed in other cell types. Oxidative stress can lead to nanoruptures in axonal membrane which is inherently protected by myelin sheath. Demyelination can exacerbate membrane damage upon the release of myelin basic protein (MBP). Neuronal repair entails calpain activity and vesicle trafficking events such as exocytosis, endocytosis, and plugging. (iv) Proximal Tubule Epithelium: Renal cells experience lipid peroxidation during I/R injury and exposure to nephrotoxins which are alleviated by antioxidants such as GPX4 and sirtuins (SIRT). Physical breaches are repaired through membrane remodeling events including microvilli shedding, caveolar endocytosis and MG53-mediated vesicle recruitment. (v) Myocytes: Mechanical stress is buffered through the dystrophin glycoprotein complex which connects the extracellular matrix to the actin cortex. This complex also anchors nitric oxide synthase (nNOS) at the cell surface to prevent ischemic injury. Upon damage, calcium influx is amplified by voltage-gated calcium channels (VGCC) and the release of lysosomal stores (MCOLN1). Calcium uptake required for successful repair is achieved by the endoplasmic reticulum and mitochondria, the latter of which promotes redox-dependent RhoA activity to drive F-actin assembly. GRAF1 promotes dysferlin at the plasma membrane where it can facilitate lysosomal exocytosis and patching. Vesicle fusion can also be achieved upon the calpain-dependent cleavage of dysferlin into a syt-like molecule. Vesicle recruitment to the wound site is promoted by MG53 and SIRT1 activity. Annexins (A) also promote wound closure by forming a highly organized repair cap which may drive constriction. Membrane remodeling is further achieved by the recruitment of regulators, such as EHD and BIN1, in addition to ESCRT-III-mediated scission