Institute of Genetics and Cancer
Institute of Genetics and Cancer

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Linking mitochondrial dysfunction to induction of the innate immune system

Yanick Crow's team, working with clinical colleagues worldwide, and together with Ashish Dhir (CGEM, IGC) and Tim Wai (institute Pasteur), have identified mutations in ATAD3A as a novel cause of interferon induction: August 2021

As brutally demonstrated by the COVID-19 pandemic, an effective immune system is essential to survival. Developed over evolutionary time, viral nucleic acid recognition represents a central pillar in the defensive armamentarium employed to combat foreign invasion. To ensure cellular homeostasis, such a strategy necessitates the efficient discrimination of pathogen-derived DNA and RNA from that of the host, and/or the physical compartmentalisation of self nucleic acids away from cytoplasmic viral nucleic acid receptors. Mitochondria represent vestigial bacteria situated in the cytosol of eukaryotic cells; and while they play a pivotal role in oxidative phosphorylation, metabolism and apoptosis, there is increasing recognition of the potential of mitochondrial nucleic acid to act as an agonist of the interferon signalling machinery.

Now, in a study just published in the Journal of Experimental Medicine, Yanick Crow's team, working with clinical colleagues worldwide, and together with Ashish Dhir (CGEM, IGC) and Tim Wai (Institut Pasteur), have identified mutations in ATAD3A as a novel cause of interferon induction. They initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. Both patients were determined to harbour a previously described de novo dominant-negative heterozygous mutation in ATAD3A. This gene encodes a protein located in the mitochondrial membrane which plays an important role in mitochondrial structure and function. ATAD3A is present in all cells and mutations have previously been associated with neurological disorders. The group went on to identify five further patients with mutations in ATAD3A, and recorded up-regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signalling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signalling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.

 

To my knowledge, this study represents the first example of mitochondrial DNA driven interferon signalling in a Mendelian disease setting. As well as highlighting mitochondria as an important source of immunogenic nucleic acid, our findings raise the interesting possibility that engagement of the innate immune system might be more relevant in ‘mitochondrial disease’ than is currently appreciated.

Professor Yanick Crow

Related Links

Original article: https://doi.org/10.1084/jem.20201560 Enhanced cGAS-STING-dependent interferon signalling associated with mutations in ATAD3A (Lepelley et al. J Exp Med 2021;218:e20201560).

Yanick Crow research group