Cryptic DNA sequences encode a temperature sensor to regulate mitochondrial suicide during neuronal differentiation

Accumulating evidence suggests that transient mitochondrial hyperactivity shapes the early stage of neuronal differentiation although mechanistic details remain largely unknown. Here, we report a mitochondrial suicide program which is activated in response to thermal flux to terminate this early stage of mitochondrial hyperactivity. A conserved stem loop at the mitochondrial origin of replication of the light strand operates as a thermal sensor, denaturing upon enhanced thermal flux and repressing the replication of the parental heavy strand of mitochondrial DNA. This triggers a quasi-replication of mitochondrial DNA characterised by replication of only the parental light strand. The non-replicated single-stranded heavy strand is then released and operates as a natural antisense DNA which sequesters complementary mRNAs encoded by the heavy strand. Subsequent degradation of the bound mRNAs by RNase H1 completes the cycle by triggering mitochondrial transcriptional decline and ultimately mitochondrial death.