Figure 5.

Cytosolic accumulation of double-stranded RNAs generated during transcription of mtDNAs activates PKR and MAVS. Cytosolic mtRNA activates RIG-I/MDA5 mediated innate immune response as well as ISR in a manner requiring the kinase PKR. Bidirectional transcription of mtDNAs generates double-stranded mtRNAs, which can escape mitochondria via BAX–BAK-mediated pore formation. Cytosolic mtRNAs stimulate innate immunity by activating RIG-I or MDA5. Once activated, RIG-I or MDA5 induces a pro-inflammatory and type I interferon immune response by increasing NF-κB and IRF3/7, respectively, in an MAVS-dependent manner. Independently, cytosolic mtRNAs bind and activate PKR-mediated ISR activation, inducing the ISR by increasing expression of the transcription factors ATF4, ATF5, and CHOP.