Annexins Bridging the Gap: Novel Roles in Membrane Contact Site Formation

Abstract

Membrane contact sites (MCS) are specialized small areas of close apposition between two different organelles that have led researchers to reconsider the dogma of intercellular communication via vesicular trafficking. The latter is now being challenged by the discovery of lipid and ion transfer across MCS connecting adjacent organelles. These findings gave rise to a new concept that implicates cell compartments not to function as individual and isolated entities, but as a dynamic and regulated ensemble facilitating the trafficking of lipids, including cholesterol, and ions. Hence, MCS are now envisaged as metabolic platforms, crucial for cellular homeostasis. In this context, well-known as well as novel proteins were ascribed functions such as tethers, transporters, and scaffolds in MCS, or transient MCS companions with yet unknown functions. Intriguingly, we and others uncovered metabolic alterations in cell-based disease models that perturbed MCS size and numbers between coupled organelles such as endolysosomes, the endoplasmic reticulum, mitochondria, or lipid droplets. On the other hand, overexpression or deficiency of certain proteins in this narrow 10–30 nm membrane contact zone can enable MCS formation to either rescue compromised MCS function, or in certain disease settings trigger undesired metabolite transport. In this “Mini Review” we summarize recent findings regarding a subset of annexins and discuss their multiple roles to regulate MCS dynamics and functioning. Their contribution to novel pathways related to MCS biology will provide new insights relevant for a number of human diseases and offer opportunities to design innovative treatments in the future.

Annexin A1, A2, A5, and A6 involvement in human pathologies

“…Annexins which associate with membranes in vitro have a common property of reversibly aggregating natural or synthetic membrane vesicles in the presence of free Ca 2+ ions. Closely related to this observation, AnxA1 complexed with S100A11 has been reported to bridge organelle membranes by contributing to the formation of organelle membrane contact sites (MCS) where AnxA6 also appears to participate in cholesterol exchange between organelles 73 . Annexins are regarded as important mediators of cell membrane trafficking, cholesterol homeostasis and flow between the plasma membrane and the membrane of intracellular organelles.…”

“…Closely related to this observation, AnxA1 complexed with S100A11 has been reported to bridge organelle membranes by contributing to the formation of organelle membrane contact sites (MCS) where AnxA6 also appears to participate in cholesterol exchange between organelles. 73 Annexins are regarded as important mediators of cell membrane trafficking, cholesterol homeostasis and flow between the plasma membrane and the membrane of intracellular organelles. The complexity of this membrane traffic might prove to be one explanation for the presence of multiple annexin paralogs found in most eukaryotes.…”

Microbiota mitochondria disorders as hubs for early age-related macular degeneration

“…MCSs or synonymously mitochondria-associated membrane (MAM) are recently identified, but well studied, special subcellular structural and functional networks of organelles, such as mitochondria, and the endoplasmic reticulum (ER), LDs, lysosomes, and peroxisomes. MCSs are characterized by specific structural and functional properties at the sites of closely apposed membranes, and proteins tethering two organelles have also been defined [ 60 ]. MCSs are dynamic structures, and these contact sites serve as unique intracellular platforms regulating a wide range of cellular reactions, including autophagy through non-vesicle contact [ 66 ].…”

“…Since RPE metabolism supports the light-induced retinoid cycle [55,56], one of the possible consequences of mitochondrial dysfunction in early AMD may manifest as a disorder of light-induced retinoid recycle. In fact, impaired dark adaptation was found in AMD [57][58][59][60]; as well as decreased sensitivity [61] and increased recovery time after photostress was found in early AMD [62,63], suggesting impaired energy production in this disease.…”

Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry

“…Several other factors of the endocytic machinery in LE/Lys linked to cholesterol and NPC1 function could also emerge as druggable antiviral targets. This includes endosomal sorting complex required for transport complexes ( Du et al, 2012 , 2013 ), late endosomal annexins ( Musiol et al, 2013 ; Kuhnl et al, 2018 ; Enrich et al, 2021 ), and Rab-GTPases ( Zang et al, 2020 ) and their regulators and effectors ( Meneses-Salas et al, 2020 ), but also proteins that link cholesterol and calcium balance in LE/Lys ( Lloyd-Evans et al, 2008 ; Enrich et al, 2021 ).…”