Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction

Significance

It is highly controversial whether secondary reactive oxygen species generated by dysfunctional mitochondria are able to diffuse across the cytoplasm to the nucleus and cause subsequent nuclear changes. We have developed a targeted chemoptogenetic technology to induce mitochondrial dysfunction by generating short-lived highly reactive singlet oxygen exclusively in the mitochondria, with precise spatiotemporal control by light stimulation. Through careful analysis of the events involving mitochondrial dysfunction and subsequent nuclear oxidative stress that resulted in specific telomere damage, we delineated the mechanism of mitochondria–telomere axis of cellular damage. Our findings revealed a fundamental mechanism underlying the pathophysiological role of mitochondrial singlet oxygen, with important ramifications for understanding the role of mitochondrial signaling in aging and cancer among other human diseases.