Excited to share our new publication in Nature Metabolism @NatMetabolism led by the fantastic @XingxiuPan, where we uncover an unexpected connection between reductive and oxidative stress. This study contains many exciting findings, and I will be highlighting different aspects of this work in a series of posts. One of the central conclusions is that the NADPH/NADP+ ratio is a critically underappreciated parameter in mitochondrial dysfunction. In this study we present SaNADK, a new xenotopic tool based on the S. aureus NAD kinase, which expands the cellular NADP(H) pool nearly six-fold! Most remarkably, together with the Peter Adams lab @AdamsBioAging, we found that increasing NADP(H) levels with SaNADK alone was sufficient to reverse age-associated hepatic transcriptomic signatures linked to metabolic dysfunction and inflammation as well as liver fibrosis highlighting the profound influence of NADP(H) metabolism on cellular aging. We also uncovered an important aspect of mitochondrial bioenergetics. We found that NADH-driven reductive stress can cause excessive reduction of the coenzyme Q pool, creating a bottleneck for multiple coenzyme Q-dependent reactions. As a consequence, electron flow through CoQ-linked systems is impaired, including DHODH activity and de novo pyrimidine biosynthesis. These findings may help explain numerous observations in the literature that have long appeared counterintuitive, namely that mild mitochondrial complex I inhibition can sometimes be beneficial. Here is the link to the study: nature.com/articles/s42255-0…