Life science
Life science, Cell biology

MAVS is energized by Mff which senses mitochondrial
metabolism via AMPK for acute antiviral immunity
Department of Biological Sciences, Graduate School of Science
Professor Naotada Ishihara
Researchmap https://researchmap.jp/10325516?lang=en

Life science

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

▍ Background & Results
Mitochondria are believed to be derived from endosymbiosis
of bacteria; however, mitochondria also act as a platform of innate
immune signaling, through mitochondrial antiviral signaling (MAVS)
protein on mitochondrial outer membrane. This antiviral platform is
not static because mitochondria are dynamic organelles, move incytoplasm and frequently divide and fuse each other. However, itremains largely unknown how the mitochondrial dynamics servesto defend infected pathogens.

Working hypothesis for how mitochondrial dysfunction leads to the suppression of
the antiviral response by the AMPK–Mff axis.

▍ Significance of the research and Future perspective
To investigate the role of mitochondria in MAVS-mediated innate
immunity, we focused on Mff, which is also located on mitochondrial outer membrane and regulates mitochondrial fission under cellular signaling. Here we found that Mff plays critical roles in formationof membrane subdomain localizing active MAVS. Under nutrition
starvation or defected in mitochondrial metabolism, Mff is phosphorylated at Ser 146 by ATP sensor AMPK, which repressed the antiviral signaling. This report reveals a novel aspect of mitochondrial
function on cellular signaling, in which mitochondrial fission factor
and innate immunity are coupled.
Mitochondrial network structures in mouse embryonic fibroblasts (MEFs). Mitochondria are stained as red and nucleus are stained as blue.

（補足図表）
Mitochondrial network structures in mouse embryonic fibroblasts (MEFs). Mitochon
are stained as red and nucleus are stained as blue.

P a t e n t
Hanada, Yuki; Ishihara, Naotada et al. MAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity. Nature
Communications. 2020; 11(1): 5711. doi: 10.1038/s41467-020-19287-7
UR
L https://mitochondria.jp/K e y w o r d mitochondria, intracellular organelle, membrane, cellar signaling
Tr e a t i s e