Dietary fatty acids fine-tune Piezo1 mechanical response

Abstract

Mechanosensitive ion channels rely on membrane composition to transduce physical stimuli into electrical signals. The Piezo1 channel mediates mechanoelectrical transduction and regulates crucial physiological processes, including vascular architecture and remodeling, cell migration, and erythrocyte volume. The identity of the membrane components that modulate Piezo1 function remain largely unknown. Using lipid profiling analyses, we here identify dietary fatty acids that tune Piezo1 mechanical response. We find that margaric acid, a saturated fatty acid present in dairy products and fish, inhibits Piezo1 activation and polyunsaturated fatty acids (PUFAs), present in fish oils, modulate channel inactivation. Force measurements reveal that margaric acid increases membrane bending stiffness, whereas PUFAs decrease it. We use fatty acid supplementation to abrogate the phenotype of gain-of-function Piezo1 mutations causing human dehydrated hereditary stomatocytosis. Beyond Piezo1, our findings demonstrate that cell-intrinsic lipid profile and changes in the fatty acid metabolism can dictate the cell’s response to mechanical cues.

Disruption of membrane cholesterol organization impairs the concerted activity of PIEZO1 channel clusters

“…When cultured with DHA, PIEZO1-GFP expressing cells displayed lower activation thresholds (Fig.7B, 7C) and an increased latency of the response (Fig.7D, SI Fig.1). In contrast with a recent study employing whole-cell patch-clamping and activation of PIEZO1 by cell indentation [20], our cell-attached patch data revealed a significant sensitization to applied suction after 24 and 48 hours of PUFA enrichment ( Table 1). The activation thresholds quantified in Table 1 are in good agreement with previously published estimates [18] [43].…”

“…All the PIEZO1 variants studied (PIEZO1-GFP, transiently transfected WT, transiently transfected R2456H mutant and N2A native) displayed slower inactivation after cholesterol removal. These results suggest that membrane cholesterol, like other lipids [20], contributes to PIEZO1 inactivation. Cholesterol depletion increases PIEZO1-GFP diffusion in live cells.…”

“…Also, cholesterol enrichment didn't sensitize the PIEZO1-GFP response or affect its kinetics (Fig.1B), indicating the additional membrane stiffening due to ordered lipids did not affect the channel response. In contrast, PIEZO1 has been reported to be desensitized following membrane stiffening by supplementation of saturated fatty acids [20] which become incorporated into membrane phospholipids. It appears therefore that PIEZO1 sensitivity is mostly affected by the stiffness of non-raft membranes.…”

“…Activation of PIEZO1 is associated with a force-from-lipids mechanism [14][15][16][17][18], where membrane forces are sufficient to drive a, yet unknown, conformational change in PIEZO1 and trigger gating. This suggests that both global effects on membrane physical properties and specific lipid interactions are likely to be essential for PIEZO1 function [19][20][21].…”

Force-dependent recruitment of Piezo1 drives adhesion maturation and calcium entry in normal but not tumor cells

“…Biophysical studies have shown that membrane bilayer tension changes can directly activate Piezo1 ion channels and the regulation of Piezo1's function has been attributed to the regulation of localized lipid bilayer tension changes 12,13 . This is supported by biophysical studies that Piezo1 is sensitive to specific lipid types 14 and the observations that Piezo1 is diffusively localized in plasma membranes of many cell lines with very few interaction partners identified 4,13,15,16 . However, an open question In the regulation of Piezo1 is the intimate involvement of the integrin-linked actin cytoskeleton in Piezo1's functions 17 .…”