Optogenetics is a cutting-edge field at the intersection of optics and genetics. This technique introduces microbial opsins, light-sensitive proteins naturally found in certain microorganisms such as algae and bacteria, into specific organelles, cells, or tissues to make them sensitive to light and thus precisely manipulable. Optogenetics has served as a powerful tool in neuroscience research, enabling scientists to dissect complex neural circuits and understand how they give rise to behavior, cognition, and disease; and is expanding its reach to other fields such as endocrinology, vision restoration, and muscle physiology.

In this episode, researcher Brandon Berry chats with Matt about the development and application of optogenetic tools to manipulate mitochondrial function in cells. He shares his experiences with engineering optogenetic proteins for mitochondrial targeting, the challenges involved in controlling mitochondrial charge, and the potential of optogenetics to manipulate mitochondrial membrane potential. He also discusses the complexities of mitochondrial dysfunction, the relationship between mitochondrial dysfunction and aging, and the role of mitochondrial membrane potential in longevity interventions, including caloric restriction.

Brandon, who is currently working on a stealth project, was a former postdoctoral research associate in Matt's lab at the University of Washington, where he did a lot of his work on developing tools for mitochondrial control. He received a PhD in Physiology from the University of Rochester.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Why Are Cells Powered by Proton Gradients?

This article discusses biochemist Peter Mitchell's model of proton gradients' role in cellular respiration. Proton gradients power the synthesis of adenosine triphosphate (ATP, an energy-providing nucleotide), providing a crucial mechanism for cellular metabolism. The article also explores how reliance on proton gradients might have constrained the evolution of complexity until the advent of eukaryotic cells, which harnessed mitochondria to control these gradients and may have facilitated the leap to multicellular life forms. Mitchell's proposition, though initially controversial, ultimately earned him a Nobel Prize and reshaped our understanding of cellular energy production.

Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins

This article describes an optogenetic approach that enables precise control of mitochondrial membrane potential through light-dependent activation of channelrhodopsins—light-sensitive proteins—targeted to the inner mitochondrial membrane. The method offers insights into cellular processes without the drawbacks of conventional pharmacological interventions.

Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance

Brandon is the lead author on this paper describing the engineering of an optogenetic technique for increasing the proton gradient, or protonmotive force, in worm mitochondria. "Charging up" mitochondria in this way has several beneficial effects for mitochondria, including increased resistance to toxins, better ATP synthesis, and hypoxia resistance.

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan

In the podcast, Brandon discusses lifespan experiments he conducted to assess the impact of optogenetic mitochondrial manipulation on longevity. This study presents his finding that optogenetically controlling mitochondria slows aging and improves measures of healthspan in worms.

Extending lifespan by rejuvenating mitochondrial membrane potential - Dr Brandon Berry

Brandon chats with Eleanor Sheekey of The Sheekey Science Show about his mtON tool and its effects on worm lifespan. He provides an introduction to mitochondria ("the best organelles ever") and its role in cells, discusses the potential role of mitochondria in aging and age-related biological processes such as cellular senescence, offers some advice for aspiring academics, and more.