Key mitochondrial functions such as ATP production, Ca2+ uptake and release, and substrate accumulation depend on the proton electrochemical gradient (ΔμH+) across the inner membrane. Although several drugs can modulate ΔμH+, their effects are hardly reversible, and lack cellular specificity and spatial resolution. Although channelrhodopsins are widely used to modulate the plasma membrane potential of excitable cells, mitochondria have thus far eluded optogenetic control. Here we describe a toolkit of optometabolic constructs based on selective targeting of channelrhodopsins with distinct functional properties to the inner mitochondrial membrane of intact cells. We show that our strategy enables a light-dependent control of the mitochondrial membrane potential (Δψm) and coupled mitochondrial functions such as ATP synthesis by oxidative phosphorylation, Ca2+ dynamics, and respiratory metabolism. By directly modulating Δψm, the mitochondria-targeted opsins were used to control complex physiological processes such as spontaneous beats in cardiac myocytes and glucose-dependent ATP increase in pancreatic β-cells. Furthermore, our optometabolic tools allow modulation of mitochondrial functions in single cells and defined cell regions.

译文

关键的线粒体功能,例如ATP的产生,Ca2的吸收和释放以及底物的积累,取决于整个内膜的质子电化学梯度 (Δ μh)。尽管几种药物可以调节 Δ μh,但它们的作用几乎是可逆的,并且缺乏细胞特异性和空间分辨率。尽管通道视紫红质被广泛用于调节可兴奋细胞的质膜电位,但线粒体迄今仍无法进行光遗传控制。在这里,我们描述了一种基于选择性靶向具有独特功能特性的通道视紫红质到完整细胞的线粒体内膜的光学构建体工具包。我们表明,我们的策略可以通过氧化磷酸化,Ca2动力学和呼吸代谢对线粒体膜电位 (Δ ψ m) 和耦合的线粒体功能 (例如ATP合成) 进行光依赖性控制。通过直接调节 Δ ψ m,线粒体靶向的视蛋白被用于控制复杂的生理过程,例如心肌细胞的自发搏动和胰腺 β 细胞中葡萄糖依赖性ATP的增加。此外,我们的光学工具可以调节单个细胞和定义的细胞区域中的线粒体功能。

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