Optogenetic mitochondrial preconditioning enhances cardiomyocyte survival under stress.

Authors

Seulhee Kim, Hwayeon Lim, Patrick Ernst, Li Zhu, Jiashuai Zhang, Min Xie, Xiaoguang Margaret Liu, Lufang Zhou

Published in

Journal of molecular and cellular cardiology. Volume 205. Pages 24-36. Epub Jun 08, 2025.

Abstract

Mitochondria play a central role in preconditioning-mediated cytoprotection, yet the specific role of mitochondrial membrane potential (ΔΨ_m) in this process remains incompletely understood. In this study, we employed a next-generation, mitochondrial-targeted optogenetic system (mOpto) to induce precisely controlled (partial and transient) ΔΨ_m depolarization and investigate its role in enhancing cardiomyocyte resilience to stress. Human AC16 cardiomyocytes expressing mOpto were subjected to low-intensity LED illumination for preconditioning, followed by exposure to stressors including FCCP, H₂O₂, or simulated ischemia-reperfusion. mOpto-preconditioned cells exhibited significantly improved viability, attenuated ΔΨ_m depolarization, and reduced reactive oxygen species (ROS) production compared to non-preconditioned controls. Notably, this cytoprotective effect occurred independently of canonical ROS signaling and mitochondrial ATP-sensitive potassium channel (mitoK_ATP) activation. Transcriptional analysis revealed coordinated mitochondrial and metabolic reprogramming, including upregulation of genes involved in lipid biosynthesis, mitochondrial quality control, energy homeostasis, and a shift toward mitochondrial fusion. Importantly, mOpto preconditioning conferred similar cytoprotective effects in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), underscoring the translational potential of this approach. These findings demonstrate that mOpto-mediated transient ΔΨ_m depolarization induces a preconditioning effect that enhances cardiomyocyte resilience through the establishment of a mitochondrial "memory" and dynamic remodeling of mitochondrial function.

PMID:
40494424
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.

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