Title: Effects of Mitochondrial Complex I Activity on Metabolism from in vitro to in vivo
Abstract: NADH provides electrons for aerobic ATP production. In cells with impaired mitochondrial complex I activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH producing pathways: glucose, glutamine, and fatty acid oxidation. Here, through deuterium tracing studies in cultured cells and mice, we show that folate dependent serine catabolism also produces substantial NADH. Strikingly, when
respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells with supraphysiological dosage of Metformin treatment, inhibition of mitochondrial serine catabolism partially normalizes NADH levels and facilitates cell growth. However, physiological treatment of metformin in vivo fails to increase organismal and tumor NADH/NAD. To have a better understanding of the effect of mitochondrial complex I activity on in vivo metabolism, we employ a mice model with engineered mitochondrial Complex I deficiency (NDUSF4-/-). Through 13 carbon and deuterium isotope tracing, we find that NDUFS4-/- mice have lower glucose and glutamine turnover rate, and serine’s contribution to NADH is elevated in pancreas and liver. A more comprehensive study of mitochondrial Complex I deficiency on whole body metabolism, especially brain metabolism, is required and could possibly pave a new avenue for clinical treatment for patients with mitochondrial diseases.
Title: Histone H3 acts a Chk1 inhibitor that controls early embryonic cell cycle
Abstract: The early embryos of many species spend the first several hours of development undergoing rapid and reductive cleavage divisions driven by maternal components. After a species-specific stereotyped number of divisions the cell cycle slows and differentiation begins in a process known as the Mid-Blastula Transition (MBT). It has long been recognized that the increasing ratio of nuclei to cytoplasm (N/C ratio) determines the timing of this transition as the reductive cleavage divisions decrease cytoplasmic volume but the genome remains the same size. Here we show that the size of the maternally provided histone pool regulates the number of divisions before the MBT and that the effect of histone levels on the cell cycle is independent of their chromatin incorporation. We find that H3 can act as a competitive inhibitor of the DNA-damage checkpoint kinase Chk1 in vitro and that mutation of a single Chk1 phosphosite in the H3 tail is sufficient to lengthen the pre-MBT cell cycles. Together these findings support a model in which non-DNA bound H3 inhibits Chk1 to promote cell cycle progression and offers a solution to the problem of N/C ratio sensing in the early embryo.