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