RT Journal Article
SR Electronic
T1 Precisely control mitochondria with light to manipulate cell fate decision
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 469668
DO 10.1101/469668
A1 Patrick Ernst
A1 Ningning Xu
A1 Jing Qu
A1 Herbert Chen
A1 Matthew S. Goldberg
A1 Victor Darley-Usmar
A1 Jianyi J. Zhang
A1 Brian O’Rourke
A1 Xiaoguang Liu
A1 Lufang Zhou
YR 2019
UL http://biorxiv.org/content/early/2019/05/29/469668.abstract
AB Mitochondrial dysfunction has been implicated in many pathological conditions and diseases. The normal functioning of mitochondria relies on maintaining the inner mitochondrial membrane (IMM) potential (a.k.a. ΔΨm) that is essential for ATP synthesis, Ca2+ homeostasis, redox balance and regulation of other key signaling pathways such as mitophagy and apoptosis. However, the detailed mechanisms by which ΔΨm regulates cellular function remain incompletely understood, partially due to difficulty of manipulating ΔΨm with spatiotemporal resolution, reversibility, or cell type specificity. To address this need, we have developed a next-generation optogenetic-based technique for controllable mitochondrial depolarization with light. We demonstrate successful targeting of the heterologous Channelrhodopsin-2 (ChR2) fusion protein to the IMM and formation of functional cationic channels capable of light-induced selective ΔΨm depolarization and mitochondrial autophagy. Importantly, we for the first time show that optogenetic-mediated mitochondrial depolarization can be well-controlled to differentially influence the fate of cells expressing mitochondrial ChR2: while sustained moderate light illumination induces substantial apoptotic cell death, transient mild light illumination elicits cytoprotection via mitochondrial preconditioning. Finally, we show that Parkin overexpression exacerbates, instead of ameliorating, mitochondrial depolarization-mediated cell death in HeLa cells. In summary, we provide evidence that the described mitochondrial-targeted optogenetics may have a broad application for studying the role of mitochondria in regulating cell function and fate decision.