Mitofusin 2, a key coordinator between mitochondrial dynamics and innate immunity

Abstract

Remodeling of mitochondrial dynamics and mitochondrial morphology plays a pivotal role in the maintenance of mitochondrial homeostasis in response to pathogenic attacks or stress stimuli. In addition to their role in metabolism and energy production, mitochondria participate in diverse biological functions, including innate immune responses driven by macrophages in response to infections or inflammatory stimuli. Mitofusin-2 (MFN2), a mitochondria-shaping protein regulating mitochondrial fusion and fission, plays a crucial role in linking mitochondrial function and innate immune responses. In this article, we review the role of MFN2 in the regulation of innate immune responses during viral and bacterial infections. We also summarize the current knowledge on the role of MFN2 in coordinating inflammatory, atherogenic, and fibrotic responses. MFN2-mediated crosstalk between mitochondrial dynamics and innate immune responses may determine the outcomes of pathogenic infections.

Mitochondria in Mycobacterium Infection: From the Immune System to Mitochondrial Haplogroups

“…Another important regulatory factor of this organelle is mitochondrial dynamics, which is the change in mitochondrial number, structure, and positioning within the cytoplasm by regulatory processes of fusion and fission and by the formation of mitochondrial networks that modulate diverse biological functions, including mitochondrial metabolism, redox balance, and cell death [ 20 , 21 , 22 ].…”

“…By this process, a partially damaged mitochondria can join other healthy mitochondria, leading to the exchange of metabolites, thus diluting the accumulated mutations in the mitochondrial DNA and being critical to sustaining mitochondrial functions [ 21 ]. Mitochondrial fusion is controlled by mitofusin-1 (MFN1) and mitofusin-2 (MFN2) GTPases, which are prerequisites for OMM fusion, and by optical atrophy GTPase 1 (OPA1), located in the IMM [ 21 , 22 , 23 ].…”

“…Mitochondrial fission is regulated by the dynamin-related protein 1 of the cytosolic GTPase protein (DRP1) through interaction with other OMM proteins such as MiD51 and MiD49, where it forms oligomeric structures surrounding the mitochondrial scission site and eventually, through GTP hydrolysis, undergoes a conformational change that results in membrane constriction and scission [ 22 , 23 ]. In addition, these proteins are essential for mitochondrial quality control and homeostasis, as well as the regulation of numerous biological processes, including immune responses [ 22 , 23 ].…”

“…Evidence from several studies suggests that molecular communication between innate immune signaling and mitochondrial dynamics regulates the processes of infection by microorganisms [ 21 , 22 ]. In particular, MFN2 appears to be a critical player in linking mitochondrial dynamics, autophagy (xenophagy and mitophagy), and innate immune responses against viruses, bacteria, and parasites, and may play an essential role in activating innate immune pathways in mitochondria-associated membranes and other specialized subcellular regions, coordinating metabolism [ 22 ].…”

“…Recent studies have shown that the AMP-activated protein kinase energy sensor interacts directly with MFN2, inducing autophagy in response to energy stress, confirming that MFN2 is essential for immune system activation during bacterial infection [ 22 ]. In addition, MFN2 is required for mitochondrial respiration and ROS production, in which it promotes cytokine and nitric oxide secretion, induces autophagy and apoptosis, and enhances antigen processing [ 22 ].…”