Extended Data Fig. 10: Model summarizing endosome-mediated disposal of dysfunctional nucleoids.

Following mtDNA replication, a signal is sent from mitochondria to the ER allowing for polymerization of ER-associated actin, which allows newly replicated nucleoids to segregate via mitochondrial fission. If problems arise during mtDNA replication or segregation as a result of mtDNA damage, no signal is sent to the ER, and actin does not associate with the ER. If nucleoids are unable to properly segregate through mitochondrial fission, a fission checkpoint is enacted (to wait for the completion of mtDNA segregation), and nucleoids accumulate at sites of replication. If not rectified, the dysfunctional nucleoids are trafficked to endosomes and are ultimately degraded by trafficking through late endosomes. However, a subset of late endosomes fails to fully mature and ultimately rupture, enabling cGAS to bind to mtDNA and trigger innate immune signalling.