Nocturnin drives mitochondrial NADP(H)/NAD(H) rhythms to regulate steroid rhythm amplitude and time metabolism

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Abstract Circadian rhythms are conserved biological timekeeping mechanisms crucial for the temporal compartmentalization of metabolic processes. However, the molecular pathways by which circadian rhythms are regulated within metabolism are not fully understood. Nocturnin (NOCT) is a highly rhythmic, clock-controlled NADP(H) phosphatase that has been implicated in numerous metabolic phenotypes. While it is known that NOCT significantly impacts the cellular NADP(H) and NAD(H) pools in vitro , NOCT’s impact on their concentrations and rhythmicity in vivo has not yet been established. In fact, the rhythmicity of NADH, NADP + , and NADPH have yet to be quantified in mammalian nucleated cells. Here, we determined both the whole cell and mitochondrial NAD(H) and NADP(H) rhythms in wild-type and Noct -/- mouse livers. Unexpectedly, we found a robust rhythm in the mitochondrial NADP(H)/NAD(H) ratio that is antiphase to the respective whole cell rhythm. While loss of NOCT increases the amplitude of the whole cell NADP(H)/NAD(H) rhythm, the mitochondrial rhythm is completely damped in Noct -/- mice. The constitutively higher relative NADP(H) within Noct -/- mitochondria drives steroidogenesis, leading to an increased amplitude of plasma corticosterone. Both the acute increase in plasma corticosterone and the disruption of mitochondrial cofactor rhythms caused by loss of NOCT lead to widespread changes in hepatic metabolism. Collectively, we found that NOCT’s control of mitochondrial NADP(H)/NAD(H) rhythms is a novel regulator of steroid amplitude and downstream metabolic rhythms.