Mitochondrial light switches: optogenetic approaches to control metabolism

Abstract

Developing new technologies to study metabolism is increasingly important as metabolic disease prevalence increases. Mitochondria control cellular metabolism and dynamic changes in mitochondrial function are associated with metabolic abnormalities in cardiovascular disease, cancer, and obesity. However, a lack of precise and reversible methods to control mitochondrial function has prevented moving from association to causation. Recent advances in optogenetics have addressed this challenge, and mitochondrial function can now be precisely controlled in vivo using light. A class of genetically encoded, light-activated membrane channels and pumps has addressed mechanistic questions that promise to provide new insights into how cellular metabolism downstream of mitochondrial function contributes to disease. Here, we highlight emerging reagents-mitochondria-targeted light-activated cation channels or proton pumps-to decrease or increase mitochondrial activity upon light exposure, a technique we refer to as mitochondrial light switches, or mt SWITCH. The mt SWITCH technique is broadly applicable, as energy availability and metabolic signaling are conserved aspects of cellular function and health. Here, we outline the use of these tools in diverse cellular models of disease. We review the molecular details of each optogenetic tool, summarize the results obtained with each, and outline best practices for using optogenetic approaches to control mitochondrial function and downstream metabolism.

Subcellular Singlet Oxygen and Cell Death: Location Matters

“…The use of ROS-generating PS to analyze signaling pathways is relatively novel but has already produced tantalizing results (Ivashchenko et al, 2011 ; Shibuya and Tsujimoto, 2012 ; Wang et al, 2012 , 2013 ; Wojtovich and Foster, 2014 ; Souslova et al, 2017 ; Hoffmann et al, 2019 ; Wojtovich et al, 2019 ; Berry and Wojtovich, 2020 ). FAP–TAPs represent a new tool potentially allowing a wide range of new photoactive reagents having multiple activating wavelengths and different ROS generating properties.…”

AMPKα2 Overexpression Reduces Cardiomyocyte Ischemia-Reperfusion Injury Through Normalization of Mitochondrial Dynamics

“…Given the beneficial effects afforded by AMPK2α overexpression on cardiomyocyte viability and function, we asked whether mitochondrial homeostasis could be sustained by AMPK2α. Firstly, we measured mitochondrial membrane potential since decreased electric potential energy is an early feature of mitochondrial damage ( Berry and Wojtovich, 2020 ). Normal cardiomyocytes exhibited high membrane potential, which displayed bright red fluorescence ( Figures 2A,B ).…”

Multilayer Genetic Circuits for Dynamic Regulation of Metabolic Pathways

“…Gene circuits based on dynamic regulation have been designed in large numbers. − , Optogenetics is flourishing in the field of metabolic engineering, and the expression levels of key genes can be finely regulated by responding to specific wavelengths of light . Berry et al constructed a mitochondrial light switch, which could use light to precisely control the expression of genes in mitochondria . Moreover, Zhao et al described a suite of optogenetic tools to trigger assembly and disassembly of metabolically active enzyme clusters, thereby redirecting metabolic flow at the protein level …”

“…51 Berry et al constructed a mitochondrial light switch, which could use light to precisely control the expression of genes in mitochondria. 90 Moreover, Zhao et al described a suite of optogenetic tools to trigger assembly and disassembly of metabolically active enzyme clusters, thereby redirecting metabolic flow at the protein level. 91 These studies demonstrate the use of single sensors to dynamically control simple pathways.…”