Lipid Metabolism at Membrane Contacts: Dynamics and Functions Beyond Lipid Homeostasis

Abstract

Membrane contact sites (MCSs), regions where the membranes of two organelles are closely apposed, play critical roles in inter-organelle communication, such as lipid trafficking, intracellular signaling, and organelle biogenesis and division. First identified as “fraction X” in the early 90s, MCSs are now widely recognized to facilitate local lipid synthesis and inter-organelle lipid transfer, which are important for maintaining cellular lipid homeostasis. In this review, we discuss lipid metabolism and related cellular and physiological functions in MCSs. We start with the characteristics of lipid synthesis and breakdown at MCSs. Then we focus on proteins involved in lipid synthesis and turnover at these sites. Lastly, we summarize the cellular function of lipid metabolism at MCSs beyond mere lipid homeostasis, including the physiological meaning and relevance of MCSs regarding systemic lipid metabolism. This article is part of an article collection entitled: Coupling and Uncoupling: Dynamic Control of Membrane Contacts.

MICOS and the mitochondrial inner membrane morphology – when things get out of shape

“…CL and PE are particularly interesting lipids as their function extends beyond providing a permeability border for hydrophilic molecules and a solvent for integral membrane proteins. The IM is an integral part of the cellular lipid biosynthesis pathway (on which excellent reviews have been published elsewhere) [151][152][153] and depends on lipid import and export.…”

Remodelling of Nucleus-Vacuole Junctions During Metabolic and Proteostatic Stress

“…We further show that recruitment of Snd3 to the junctions and concomitant NVJ expansion is controlled by central glucose signalling pathways, establishing a link between metabolic rewiring and contact site dynamics (Figure 2A). The protein kinase A (PKA) as well as the AMP-dependent kinase Snf1 represent two evolutionary conserved branches of the metabolic signalling network, activated in response to high glucose or glucose depletion, respectively (Hedbacker and Carlson, 2008; Zhang and Cao, 2017; Stasyk and Stasyk, 2019). Mimicking the presence of glucose via (i) genetic inactivation of the inhibitory subunit of PKA, resulting in hyperactive PKA signalling, or (ii) disruption of AMP-dependent Snf1 signalling, prevented Snd3 targeting to and Nvj1 enrichment at the contact sites despite glucose depletion (Tosal-Castano et al., 2021).…”

“…In an elegant approach using multi-colour time-lapse imaging and automated single-cell analysis, they monitored protein-fluorophore chimeras, including Nvj1, throughout growth in high glucose, acute starvation for several hours and subsequent glucose replenishment. To maintain cellular viability upon abrupt starvation, cells need to quickly adapt by rewiring cellular homeostasis and exit cell cycle, which requires central metabolic signalling networks, including an inhibition of PKA signalling and the activation of the AMPK/Snf1 pathway (Zhang and Cao, 2017). Interestingly, Wood et al .…”

“…For microbial cells, evolutionary success depends on their ability to sense and rapidly adapt to fluctuating availability of nutrients or exposure to stress. Cellular metabolism needs to be adjusted to allow growth and division in times of plenty and to sustain homeostasis and stress response when nutrients are limiting (Zhang and Cao, 2017). Optimal resource allocation requires sensing and signalling of extracellular conditions and a subsequent metabolic rewiring and cellular remodelling to adjust organellar functions.…”

“…These sites serve as metabolic hubs and rapidly change size and abundance in response to various types of external and internal cues, thereby optimizing and fine-tuning organellar function to respective cellular needs. Contact sites allow the transfer of information in form of ions, lipids or small metabolites between distinct cellular subcompartments, thus providing a connection between spatially separated biochemical reactions within each organellar microenvironment (Xu and Huang, 2020). In cooperation with classical signalling pathways and vesicular transport, this form of interorganellar communication links the metabolic activities in different organelles to guarantee overall cellular homeostasis.…”