Plasma membrane integrity in health and disease: significance and therapeutic potential

Abstract

Maintenance of plasma membrane integrity is essential for normal cell viability and function. Thus, robust membrane repair mechanisms have evolved to counteract the eminent threat of a torn plasma membrane. Different repair mechanisms and the bio-physical parameters required for efficient repair are now emerging from different research groups. However, less is known about when these mechanisms come into play. This review focuses on the existence of membrane disruptions and repair mechanisms in both physiological and pathological conditions, and across multiple cell types, albeit to different degrees. Fundamentally, irrespective of the source of membrane disruption, aberrant calcium influx is the common stimulus that activates the membrane repair response. Inadequate repair responses can tip the balance between physiology and pathology, highlighting the significance of plasma membrane integrity. For example, an over-activated repair response can promote cancer invasion, while the inability to efficiently repair membrane can drive neurodegeneration and muscular dystrophies. The interdisciplinary view explored here emphasises the widespread potential of targeting plasma membrane repair mechanisms for therapeutic purposes.

Fig. 1. Schematic illustrating loss of membrane integrity under different physiological and pathological context and the common downstream events (calcium influx and membrane repair).

Skeletal myocytes (first section of the grey boxes) undergo the danger of disrupting their sarcolemma during eccentric contractions under physiological conditions. Mutations in genes that produce fragile membranes and those that encode repair proteins are prone to membrane disruptions. Cardiac myocytes (second section) are also subjected to membrane disruptions during contraction, but during myocardial infarction the sarcolemma becomes subjected to injury. Pore-mediated injuries can affect all cell types. Under physiological conditions pores are formed by complement proteins produced by dendritic cells, as these arrange into the membrane attack complex. Under pathological contexts, toxins released from pore-forming bacteria damage membranes (third section). From a physiological background, age-dependent changes in the membranes of neurons drive loss of integrity. This phenomenon is also seen in brain injury and neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease) (fourth section). Cells that migrate through dense tissue also compromise their membranes. This includes fibroblasts and dendritic cells as they migrate through extracellular matrices and into blood vessels, as well as cancer cells during metastasis (fifth section). Irrespective of the source of damage, all injuries result in an abnormal influx of calcium into the intracellular space. This drives membrane repair mechanisms, which consist of membrane replacement and fusion strategies (e.g. exocytosis-mediated fusion of lysosomes with the damaged plasma membrane for patch repair or tension relief), removal of damaged membrane (including ectosome shedding or endocytosis-mediated repair), or protein-centric repair mechanisms (e.g. formation of 2D arrays by repair proteins to promote wound constriction).

Fig. 2. Loss of membrane integrity in neurodegenerative diseases.

In Alzheimer’s disease and Parkinson’s disease, the disease proteins amyloid-β and α-synuclein, respectively, aggregate from monomers to aggregates, transitioning from intrinsically unfolded or α-helical structures to β-sheet-rich structures. Different mechanisms of protein-induced loss of membrane integrity are represented. a Protein–lipid interactions and lipid-mediated conformational changes result in protein incorporation into the membrane. This increases surface pressure and membrane rigidity, and can promote membrane thinning and deformation. b, c Proteins may induce lipids to reposition out of the plane of the membrane, resulting in membrane thinning (b) and curvature (c). d During aggregation, oligomers extract phospholipids from the bilayer and incorporate into the growing fibrils, causing membrane rupture. e Amyloidogenic proteins form pores in membranes. α-Syn forms pores rich in α-helical or β-sheet structures (toroidal and barrel models, respectively). All these mechanisms result in an influx of calcium from the extracellular environment and an efflux of cytosolic content.