Membrane Repair: Mechanisms and Pathophysiology

Abstract

Eukaryotic cells have been confronted throughout their evolution with potentially lethal plasma membrane injuries, including those caused by osmotic stress, by infection from bacterial toxins and parasites, and by mechanical and ischemic stress. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Calcium has been identified as the key trigger to activate an effective membrane repair response that utilizes exocytosis and endocytosis to repair a membrane tear, or remove a membrane pore. We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Collective evidence reveals membrane repair employs primitive yet robust molecular machinery, such as vesicle fusion and contractile rings, processes evolutionarily honed for simplicity and success. Yet to be fully understood is whether core membrane repair machinery exists in all cells, or whether evolutionary adaptation has resulted in multiple compensatory repair pathways that specialize in different tissues and cells within our body.

Triggered recruitment of ESCRT machinery promotes endolysosomal repair

“…Calcium is an established trigger of cellular responses to membrane damage at the plasma membrane (13), and is required to recruit ESCRTs to plasma membrane wounds (15, 16). Because endolysosomes are calcium-storing organelles and rupturing them elevates intracellular calcium (27, 28), we wondered whether ESCRT recruitment to damaged endolysosomes might similarly be regulated by calcium.…”

In vitro and ex vivo strategies for intracellular delivery

“…Along with the intended influx of cargo, there is the entry of Ca 2+ , and the efflux of K + , proteins, amino acids, metabolites, ATP, and other cytoplasmic contents to contend with 70 . Inundation with reactive oxygen species and other toxic molecules may cause further damage to endogenous proteins and biomolecules 49 .…”

“…Inundation with reactive oxygen species and other toxic molecules may cause further damage to endogenous proteins and biomolecules 49 . Thus, cells urgently deploy repair pathways to reseal membrane disruptions and recover from the damage imposed (see recent reviews [70][71][72][73][74] ).…”

“…There is a marked consistency in the properties of the repair pathways, regardless of whether the source of damage is electrical, mechanical, optical, or even chemical 70,74 . Instead, membrane recovery is thought to depend on disruption size, collateral damage, temperature, composition of the extracellular medium, and cell type.…”

“…3c). This is followed by a longer phase involving restoration of cytoplasmic composition, stress response and possible alterations in transcription 70 . The influx and retention of molecules will depend on the size, lifetime and distribution of disruptions, as well as the properties of cargo molecules and their interaction with the cell 50 .…”