From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

Abstract

The volumes of a cell [cell volume (CV)] and its organelles are adjusted by osmoregulatory processes. During pinocytosis, extracellular fluid volume equivalent to its CV is incorporated within an hour and membrane area equivalent to the cell’s surface within 30 min. Since neither fluid uptake nor membrane consumption leads to swelling or shrinkage, cells must be equipped with potent volume regulatory mechanisms. Normally, cells respond to outwardly or inwardly directed osmotic gradients by a volume decrease and increase, respectively, i.e., they shrink or swell but then try to recover their CV. However, when a cell death (CD) pathway is triggered, CV persistently decreases in isotonic conditions in apoptosis and it increases in necrosis. One type of CD associated with cell swelling is due to a dysfunctional pinocytosis. Methuosis, a non-apoptotic CD phenotype, occurs when cells accumulate too much fluid by macropinocytosis. In contrast to functional pinocytosis, in methuosis, macropinosomes neither recycle nor fuse with lysosomes but with each other to form giant vacuoles, which finally cause rupture of the plasma membrane (PM). Understanding methuosis longs for the understanding of the ionic mechanisms of cell volume regulation (CVR) and vesicular volume regulation (VVR). In nascent macropinosomes, ion channels and transporters are derived from the PM. Along trafficking from the PM to the perinuclear area, the equipment of channels and transporters of the vesicle membrane changes by retrieval, addition, and recycling from and back to the PM, causing profound changes in vesicular ion concentrations, acidification, and—most importantly—shrinkage of the macropinosome, which is indispensable for its proper targeting and cargo processing. In this review, we discuss ion and water transport mechanisms with respect to CVR and VVR and with special emphasis on pinocytosis and methuosis. We describe various aspects of the complex mutual interplay between extracellular and intracellular ions and ion gradients, the PM and vesicular membrane, phosphoinositides, monomeric G proteins and their targets, as well as the submembranous cytoskeleton. Our aim is to highlight important cellular mechanisms, components, and processes that may lead to methuotic CD upon their derangement.

Local Membrane Curvature Pins and Guides Excitable Membrane Waves in Chemotactic and Macropinocytic Cells - Biomedical Insights From an Innovative Simple Model

“…While this pathway is also observed in diverse range of mammalian cells too, such as immune cells, endothelial and epithelial cells (Lin et al, 2020), they also play an essential role in cancer cells as reviewed in Ha et al (2016), Recouvreux and Commisso (2017), Commisso (2019), andRitter et al (2021). It has been identified that macropinocytosis is a mechanism by which cancer cells support their unique metabolic needs (Commisso et al, 2013), and has therefore increased the interest for anticancer therapies (Ritter et al, 2021;Song et al, 2021). The findings presented here open an interesting new aspect to macropinocytosis that suggests relevance to cancer cells too, as PIP3 domain dynamics are observed as self-organizing waves that are prone to be pinned and guided by strongly bended membranes, just as observed during the formation of macropinocytic cups (Veltman et al, 2016).…”

“…Following on that, another important aspect of PIP3 dynamics is the macropinocytosis (Buczynski et al, 1997 ; Hoeller et al, 2013 ; Veltman et al, 2016 ), which is a unique pathway of endocytosis to internalize large amounts of extracellular fluid, solutes and membrane (Lin et al, 2020 ). In non-mammalian cells, such as Dictyostelium cells, macropinocytosis requires PIP3 and the persistent activation of Ras Williams et al ( 2019 ) to form patches in macropinosomes Ritter et al ( 2021 ). While this pathway is also observed in diverse range of mammalian cells too, such as immune cells, endothelial and epithelial cells (Lin et al, 2020 ), they also play an essential role in cancer cells as reviewed in Ha et al ( 2016 ), Recouvreux and Commisso ( 2017 ), Zhang and Commisso ( 2019 ), and Ritter et al ( 2021 ).…”

“…In non-mammalian cells, such as Dictyostelium cells, macropinocytosis requires PIP3 and the persistent activation of Ras Williams et al ( 2019 ) to form patches in macropinosomes Ritter et al ( 2021 ). While this pathway is also observed in diverse range of mammalian cells too, such as immune cells, endothelial and epithelial cells (Lin et al, 2020 ), they also play an essential role in cancer cells as reviewed in Ha et al ( 2016 ), Recouvreux and Commisso ( 2017 ), Zhang and Commisso ( 2019 ), and Ritter et al ( 2021 ). It has been identified that macropinocytosis is a mechanism by which cancer cells support their unique metabolic needs (Commisso et al, 2013 ), and has therefore increased the interest for anticancer therapies (Ritter et al, 2021 ; Song et al, 2021 ).…”

Сell death and its significance in reproductive pathology

“…These processes in the cell occur against the background of minimal energy expenditure. Modern diagnosis of cell necrosis is based on the deteсе of lactate dehydrogenase activity and the use of specific cell-impermeamble DNA binding dyes (Rogers et al, 2017;Orning et al, 2017;Rijal et al, 2018).…”

“…In addition, cell-free DNA and DNA neutrophils, the resulting protein complexes can be detected using PicoGreen ® and ELISA. Both morphology and cellrelated components of NETosis can be detected by flow cytometry (Zhelavskyi, 2015;Rijal et al, 2018).…”