Mitochondria-associated membranes (MAMs) and inflammation

Abstract

The endoplasmic reticulum (ER) and mitochondria are tightly associated with very dynamic platforms termed mitochondria-associated membranes (MAMs). MAMs provide an excellent scaffold for crosstalk between the ER and mitochondria and play a pivotal role in different signaling pathways that allow rapid exchange of biological molecules to maintain cellular health. However, dysfunctions in the ER-mitochondria architecture are associated with pathological conditions and human diseases. Inflammation has emerged as one of the various pathways that MAMs control. Inflammasome components and other inflammatory factors promote the release of pro-inflammatory cytokines that sustain pathological conditions. In this review, we summarize the critical role of MAMs in initiating inflammation in the cellular defense against pathogenic infections and the association of MAMs with inflammation-mediated diseases.

Fig. 1. Mitochondria-associated ER membranes are important sites for NLRP3 inflammasome activation

Under non-stimulatory conditions, most NLRP3 protein localizes to cytoplasmic granular structures. Stimulation with extracellular ATP and particulate/crystalline activators, which lead to lysosomal rupture, DAMPs, and PAMPs, triggers the generation of ROS that activate NLRP3. Once activated, NLRP3 recruits an adaptor protein called apoptosis-associated speck-like protein containing a CARD (ASC) and redistributes to the MAM fraction. Thus, upon pro-inflammatory stimuli, NLRP3 oligomerizes and exposes its effector domain to interact with ASC, which in turn recruits pro-caspase-1. Finally, activated caspase-1 cleaves pro-IL-1β to generate mature IL-1β. ASC apoptosis-associated speck-like protein containing a CARD, IL-1β interleukin-1 beta, NLRP3 NOD-like receptor protein 3

Fig. 2. Schematic representation of MAMs in the antiviral response

MAVS is located on the outer mitochondrial membrane (OMM) and mediates antiviral signaling by inducing the recruitment of several members of the TRAF family. Moreover, MAVS interacts with the helicases RIG-1 or MDA5 (melanoma differentiation-associated gene 5). Upon virus infection, MAVS and RIG-I create a complex with STING that increases the interferon response. Gp78 can be considered another MAVS interactor that regulates MAVS-mediated antiviral signaling. The UL37 protein from HCMV traffics into the MAMs during permissive infection and induces alteration of the Ca²⁺ signaling. Infection with HIV-1 directly targets MAMs leading to mitochondrial polarization and apoptosis. Infection with DENV results in the compromised integrity of MAMs and reduced RIG-1-dependent IFN response. DENV dengue virus, ER endoplasmic reticulum, HCMV human cytomegalovirus of the large family of DNA viruses Herpesviridae, HCV hepatitis C virus, HIV-1 immunodeficiency virus 1, I IFN interferon I, IRF3 interferon regulatory factor 3, MAVS mitochondrial antiviral-signaling protein, MCU mitochondrial Ca²⁺ uniporter, NF-kB nuclear factor-κB, NS3 nonstructural protein 3, NS4 nonstructural protein 4, RIG-I retinoic acid-inducible gene-I protein, ROS reactive oxygen species, Sig1-R sigma-1 receptor, STING Stimulator of interferon genes, Vpr viral protein R

Fig. 3. A hypothetical model of how bacterial pathogens could affect MAM-mediated cellular processes

MAMs are a molecular platform involved in several cellular processes. As such, different pathogenic bacteria could alter these signaling pathways. Interestingly, once released into the extracellular space, mitochondrial DAMPs of bacterial origin, such as cardiolipin and NFPs, can stimulate the innate and adaptive immune responses. ACAT enzyme acyl-CoA:cholesterol acyltransferase, CASP2 caspase 2, Ca²⁺ calcium, IP3R3 inositol 1,4,5-triphosphate receptor type 3, MCU mitochondrial Ca²⁺ uniporter, NFPs N-formyl peptides, NLRP3 NOD-like receptor protein 3, PE phosphatidylethanolamine, PS phosphatidylserine, PSD phosphatidylserine decarboxylase, PSS1 phosphatidylserine synthase-1, PSS2 phosphatidylserine synthase-2, Sig1-R sigma-1 receptor, TXNIP thioredoxin-interacting protein

Fig. 4. Involvement of the ER–mitochondria interface in the pathogenesis of neuronal disorders, diabetes, and cardiac and vascular diseases

The activities of several MAM proteins linked to inflammation have been found to be disrupted during the pathogenesis of a number of human diseases. See text for further details