MAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity

Abstract

Mitochondria are multifunctional organelles that produce energy and are critical for various signaling pathways. Mitochondrial antiviral signaling (MAVS) is a mitochondrial outer membrane protein essential for the anti-RNA viral immune response, which is regulated by mitochondrial dynamics and energetics; however, the molecular link between mitochondrial metabolism and immunity is unclear. Here we show in cultured mammalian cells that MAVS is activated by mitochondrial fission factor (Mff), which senses mitochondrial energy status. Mff mediates the formation of active MAVS clusters on mitochondria, independent of mitochondrial fission and dynamin-related protein 1. Under mitochondrial dysfunction, Mff is phosphorylated by the cellular energy sensor AMP-activated protein kinase (AMPK), leading to the disorganization of MAVS clusters and repression of the acute antiviral response. Mff also contributes to immune tolerance during chronic infection by disrupting the mitochondrial MAVS clusters. Taken together, Mff has a critical function in MAVS-mediated innate immunity, by sensing mitochondrial energy metabolism via AMPK signaling.

Dysfunctional telomeres through mitostress‐induced cGAS/STING activation to aggravate immune senescence and viral pneumonia

“…The currently ongoing respiratory infections are mostly from RNA viruses such as IAV and SARS‐CoV‐2, which are thought to be sensed by the RNA‐sensing (MDA/RIG‐I) pathway rather than the DNA‐sensing (cGAS/STING) system. However, emerging data have shown that the infectious agents might, through directly or indirectly acting on mitochondria, participate in the STING‐mediated pathway (Hanada et al, 2020). The strength and duration of STING pathway appear to be determined by both cellular intrinsic signals and pathogen‐derived cues converging at the mitochondria.…”

Cigarette Smoke Extract Disturbs Mitochondria-Regulated Airway Epithelial Cell Responses to Pneumococci

“…The CSE-induced impairment in IFN responses and consequent dampened innate immune suppression may be triggered through downregulation of RIG-I, MDA-5 and TLR3 via IKB kinase epsilon (IKBKE)-mediated regulation of interferon regulatory factors (IRFs), as observed by downregulation of RIG-I , MDA-5 , and TLR3 genes upon CSE stimulation. Additionally, CSE-induced attenuation of interferon responses may be triggered by increased levels of mitochondrial antiviral signaling (MAVS) inhibitors such as E3 ligases Trim29, Smurf1/2, March5 that degrade MAVS or by NLRX1-mediated MAVS inhibition [ 37 ]. This NLRX-mediated inhibition of MAVS and downregulation in interferon response is reported to be regulated via the Tu mitochondrial translation elongation factor (TUFM) [ 38 ].…”

The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

“…Moreover, miR-33/33* was found in macrophages infected with vesicular stomatitis virus (VSV) to inhibit MAVS accumulation by targeting AMPK, thereby inhibiting RIG-I signaling ( Liu et al, 2021a ). Other studies have also shown that AMPK decentralizes MAVS distribution in mitochondria and inhibits proinflammatory factors (IFN-β and IL-6; Hanada et al, 2020 ). Therefore, we suggest that AMPK may inhibit MAVS accumulation by regulating HK2 or lactate, but the specific mechanism needs further experimental proof.…”