Among reactive oxygen species (ROS), H2O2 alone acts as a signaling molecule that promotes diverse phenotypes depending on the intracellular concentration. Mitochondria are a putative source of H2O2 as well as a site of redox signaling, and mitochondrial dysfunction has been implicated in diseases such as cancer. A genetically-encoded H2O2 generator, D-amino acid oxidase (DAAO), was targeted to the mitochondria of human cells; this was paired with a genetically encoded sensor of H2O2, HyPer-mito, and was used to investigate a range of H2O2 doses over time. Mitochondrially-targeted perturbations induced significant cell death in a concentration- and time-dependent manner. This work presents the first oxidant-specific perturbation of mitochondria in order to investigate cell death, and it reveals a marked sensitivity of this organelle to increases in H2O2 in comparison with prior studies that targeted the cytosol. These data have implications for the targeting of redox-based chemotherapeutics.

Investigating H2O2-induced cell death using a tunable, localized generator of peroxide in mammalian cell mitochondria

255th National Meeting (2018)

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