Mitochondria are descended from bacteria that invaded cells 1.5 billion years ago and never left. The mitochondrial genome is like that of bacteria: circular double-stranded DNA, only smaller. And just like the genome of bacteria, RNA can be made from both strands of mitochondrial DNA – which results in the formation of dsRNA. Fortunately there are systems in place to make sure that this dsRNA does not cause excessive interferon (IFN) production, which would damage the cell.
The innate immune system of vertebrates evolved to detect foreign invaders, such as viruses, by their molecular patterns. For example, viral double-stranded RNA (dsRNA) made during infection can be detected by the innate immune system, leading to the production of antiviral proteins. Because of this sensing system, it is quite important that any dsRNA produced by the cell does not activate IFN production.
Two mitochondrial proteins are the key to protecting the cell from dsRNA. One is SUV3, a protein that can unwind dsRNA. The other is polynucleotide phosphorylase (PNPase), an exonuclease that degrades RNA. Depletion of either protein causes massive accumulation of dsRNA in mitochondria. When PNP is depleted, this dsRNA moves to the cytoplasm. Thus another function of PNPase must be to prevent the movement of dsRNA from the mitochondrion to the cytoplasm.
Uninfected cells do not produce large quantities of IFN and the interferon-stimulated genes (ISGs). However when PNP is depleted, IFN and ISGs are induced as a consequence of dsRNA moving from mitochondria to the cytoplasm. The sensor for this dsRNA is the cytoplasmic protein MDA5, which also detects viral dsRNA, leading to IFN induction.
Here’s another way to look at these findings: cells cannot prevent mitochondria from producing dsRNA from their circular DNA genome. Instead, two mitochondrial proteins have evolved that keeps dsRNA formation to a minimum, and prevents it from entering the cytoplasm, where it would be sensed by MDA5.
Overproduction of IFN, in the absence of viral infection, leads to a condition called type I interferonopathy which can lead to serious inflammatory disease and death. Mutations in the gene encoding PNPase can cause this disease. Primary fibroblasts from four patients with mutations in the PNPase gene all accumulate dsRNA in mitochondria and cytoplasm. These patients also over-produce IFN and ISGs.
As might be expected, type I interferonopathies are also associated with mutations in the gene encoding the dsRNA sensor MDA5. These mutations lead to amino acid changes that make the sensor to be hyperactive, causing chronic production of IFN.
Besides mitochondria, there are other sources of dsRNA in our cells. Transcripts of the highly repeated Alu elements in the genome are structured, with double-stranded regions that are detected by MDA5, triggering IFN production. They are kept in check by an enzyme called adenosine deaminase 1 (ADAR1), which converts A to I in the RNAs, preventing base pairing and formation of dsRNA. Humans with mutations in the gene encoding ADAR1 also display type I interferonopathies.
If cells have ways to prevent sensing of dsRNAs, you can bet that so do viruses. These range from never releasing dsRNA from the viral particle, shielding them from cytoplasmic sensors (reoviruses), to encoding viral proteins that inactivate the sensors or the downstream effectors of IFN induction.