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Skinner, Owen

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Skinner

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Skinner, Owen
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    Metabolic Regulation of Species-Specific Developmental Rates
    (Nature Publishing Group, 2023-01-04) Diaz Cuadros, Margarete; Miettinen, Teemu; Skinner, Owen; Sheedy, Dylan; Diaz Garcia, Carlos; Gapon, Svetlana; Hubaud, Alexis; Yellen, Gary; Manalis, Scott R.; Oldham, William; Pourquie, Olivier
    Animals display significant inter-species variation in the rate of embryonic development despite broad conservation of the overall sequence of developmental events. Differences in biochemical reaction speeds, including the rates of protein production and degradation, are thought to be responsible for species-specific rates of development [1-3]. However, the cause of differential biochemical reaction speeds between species remains unknown. Using pluripotent stem cells, we have established an in vitro system that recapitulates the two-fold difference in developmental rate between mouse and human embryos. This system provides a quantitative measure of developmental speed as revealed by the period of the segmentation clock, a molecular oscillator associated with the rhythmic production of vertebral precursors. Using this system, we showed that mass-specific metabolic rates scale with developmental rate and are therefore elevated in mouse cells compared to human cells. We further showed that reducing these metabolic rates by inhibiting the electron transport chain slowed down the segmentation clock by impairing the cellular NAD+/NADH redox balance and, further downstream, lowering the global rate of protein synthesis. Conversely, increasing the NAD+/NADH ratio in human cells by overexpression of the NADH oxidase LbNOX increased translation rate and accelerated the segmentation clock. These findings represent a starting point for the manipulation of developmental rate, with multiple translational applications including the acceleration of human PSCs differentiation for disease modeling and cell-based therapies.
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    An Engineered Enzyme That Targets Circulating Lactate to Alleviate Intracellular NADH:NAD+ Imbalance
    (Springer Science and Business Media LLC, 2020-01-13) Patgiri, Anupam; Skinner, Owen; Miyazaki, Yusuke; Schleifer, Grigorij; Marutani, Eizo; Shah, Hardik; Sharma, Rohit; Goodman, Russell; To, Tsz-Leung; Bao, Xiaoyan; Ichinose, Fumito; Zapol, Warren; Mootha, Vamsi
    An elevated intracellular NADH/NAD+ ratio, or “reductive stress,” has been associated with multiple diseases, including disorders of the mitochondrial electron transport chain (ETC). As the intracellular NADH/NAD+ ratio can be in near-equilibrium with the circulating lactate/pyruvate ratio, we hypothesized that reductive stress could be alleviated by oxidizing extracellular lactate into pyruvate. We engineered LOXCAT, a fusion of bacterial lactate oxidase (LOX) and catalase (CAT), which irreversibly converts lactate and oxygen to pyruvate and water. Addition of recombinant LOXCAT to the media of cultured human cells with a defective ETC was able to decrease the extracellular lactate/pyruvate ratio, normalize the intracellular NADH/NAD+ ratio, upregulate glycolytic ATP production, and restore cellular proliferation. In mice, tail-vein injected LOXCAT reduced circulating lactate/pyruvate ratio, blunted a metformin-induced rise in blood lactate/pyruvate, and improved NADH/NAD+ balance in heart and brain. Our study lays the groundwork for a class of injectable therapeutic enzymes that alleviate intracellular redox imbalances by directly targeting circulating redox-coupled metabolites.