bims-mitinf 2019-02-10 papers

Issue of 2019‒02‒10
three papers selected by
Prafull Kumar Singh
University of Freiburg Medical Center

J Cell Commun Signal. 2019 Feb 04.

Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response.

Abhishek Mohanty, Rashmi Tiwari-Pandey, Nihar R Pandey.

Mitochondria, the dynamic organelles and power house of eukaryotic cells function as metabolic hubs of cells undergoing continuous cycles of fusion and fission. Recent findings have made it increasingly apparent that mitochondria essentially involved in energy production have evolved as principal intracellular signaling platforms regulating not only innate immunity but also inflammatory responses. Perturbations in mitochondrial dynamics, including fusion/fission, electron transport chain (ETC) architecture and cristae organization have now been actively correlated to modulate metabolic activity and immune function of innate and adaptive immune cells. Several newly identified mitochondrial proteins in mitochondrial outer membrane such as mitochondrial antiviral signaling protein (MAVS) and with mitochondrial DNA acting as danger-associated molecular pattern (DAMP) and mitochondrial ROS generated from mitochondrial sources have potentially established mitochondria as key signaling platforms in antiviral immunity in vertebrates and thereby orchestrating adaptive immune cell activations respectively. A thorough understanding of emerging and intervening role of mitochondria in toll-like receptor-mediated innate immune responses and NLRP3 inflammasome complex activation has gained lucidity in recent years that advocates the imposing functions of mitochondria in innate immunity. Fascinatingly, also how the signals stemming from the endoplasmic reticulum co-operate with the mitochondria to activate the NLRP3 inflammasome is now looked ahead as a stage to unravel as to how different mitochondrial and associated organelle stress responses co-operate to bring about inflammatory consequences. This has also opened avenues of research for revealing mitochondrial targets that could be exploited for development of novel therapeutics to treat various infectious, inflammatory, and autoimmune disorders. Thus, this review explores our current understanding of intricate interplay between mitochondria and other cellular processes like autophagy in controlling mitochondrial homeostasis and regulation of innate immunity and inflammatory responses.

Keywords: Inflammasome; Inflammation; Innate immune response; Mitochondrial dynamics; Mitophagy; NLRP3

DOI: https://doi.org/10.1007/s12079-019-00507-9

Mol Cell. 2019 Jan 23. pii: S1097-2765(19)30002-4. [Epub ahead of print]

Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1.

Shiori Sekine, Chunxin Wang, Dionisia P Sideris, Eric Bunker, Zhe Zhang, Richard J Youle.

Mutations in PTEN-induced kinase 1 (PINK1) can cause recessive early-onset Parkinson's disease (PD). Import arrest results in PINK1 kinase activation specifically on damaged mitochondria, triggering Parkin-mediated mitophagy. Here, we show that PINK1 import is less dependent on Tim23 than on mitochondrial membrane potential (ΔΨm). We identified a negatively charged amino acid cluster motif that is evolutionarily conserved just C-terminal to the PINK1 transmembrane. PINK1 that fails to accumulate at the outer mitochondrial membrane, either by mutagenesis of this negatively charged motif or by deletion of Tom7, is imported into depolarized mitochondria and cleaved by the OMA1 protease. Some PD patient mutations also are defective in import arrest and are rescued by the suppression of OMA1, providing a new potential druggable target for PD. These results suggest that ΔΨm loss-dependent PINK1 import arrest does not result solely from Tim23 inactivation but also through an actively regulated "tug of war" between Tom7 and OMA1.

Keywords: OMA1; TIM23 complex; TOM complex; mitochondrial protease; mitophagy

DOI: https://doi.org/10.1016/j.molcel.2019.01.002

FEBS J. 2019 Feb 04.

MAVS polymers smaller than 80 nm induce mitochondrial membrane remodeling and interferon signaling.

Ming-Shih Hwang, Jérôme Boulanger, Jonathan D Howe, Anna Albecka, Mathias Pasche, Leila Mureşan, Yorgo Modis.

Double-stranded RNA (dsRNA) is a potent proinflammatory signature of viral infection and is sensed primarily by RIG-I-like receptors (RLRs). Oligomerization of RLRs following binding to cytosolic dsRNA activates and nucleates self-assembly of the mitochondrial antiviral signaling protein (MAVS). In the current signaling model, the caspase recruitment domains of MAVS form helical fibrils that self-propagate like prions to promote signaling complex assembly. However, there is no conclusive evidence that MAVS forms fibrils in cells or with the transmembrane anchor present. We show here with super-resolution light microscopy that MAVS activation by dsRNA induces mitochondrial membrane remodeling. Quantitative image analysis at imaging resolutions as high as 32 nm shows that in the cellular context MAVS signaling complexes and the fibrils within them are smaller than 80 nm. The transmembrane domain of MAVS is required for its membrane remodeling, interferon signaling and proapoptotic activities. We conclude that membrane tethering of MAVS restrains its polymerization and contributes to mitochondrial remodeling and apoptosis upon dsRNA sensing. This article is protected by copyright. All rights reserved.

Keywords: STORM ; cell death; innate immunity; pathogen-associated molecular pattern (PAMP); signal transduction

DOI: https://doi.org/10.1111/febs.14772