Editors' ChoiceCell Biology

Going nuclear for long life

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Sci. Signal.  16 Jun 2015:
Vol. 8, Issue 381, pp. ec158
DOI: 10.1126/scisignal.aac7866

By regulating metabolism, mitochondria supply cells with energy, modulate cellular redox balance, and affect organismal longevity. CLK-1 in worms and COQ7 in humans are targeted to mitochondria, are cleaved to become trapped in these organelles, and then function in the biosynthesis of ubiquinone, a cofactor in the electron transport chain. Worms and mice lacking the respective genes exhibit altered mitochondrial metabolism and increased life span. Monaghan et al. detected the uncleaved form of these proteins in the nucleus. The proportion of the uncleaved, nuclear form was increased by exposing worms or HeLa cells to hydrogen peroxide and was reduced by exposure to an antioxidant. Replacing COQ7 with a R28A mutant that could not localize to the nucleus reduced proliferation without affecting ubiquinone production. Adding a single copy of a nuclear-targeted, truncation mutant of CLK-1 (CLK-1nuc) in clk-1-null worms did not rescue ubiquinone production but did reduce the amount of reactive oxygen species (ROS). Paraquat causes redox stress by inhibiting mitochondrial respiration, and more CLK-1nuc worms survived paraquat exposure than clk-1-null worms.CLK-1nuc partially rescued and wild-type CLK-1 completely rescued the increased life span of clk-1-null worms. Nuclear CLK-1 or COQ7 stimulated the expression of some genes (for example, that encoding mitochondrial glutaminase) and repressed that of others (for example, those encoding the oxidoreductase WWOX, superoxide dismutase, and the proapoptotic mitochondrial protease HTRA2). Expression of the gene encoding the proapoptotic mitochondrial protease HTRA2 was increased in cells expressing only R28A COQ7 (mitochondrial COQ7), and redox-stress-induced death of these cells with only was reduced by inhibition of this protease. Nuclear CLK-1 or COQ7 inhibited the UPRmt (mitochondrial unfolded protein response). Collectively, the data suggested that the balance of nuclear and mitochondrial CLK-1 and COQ7 influences the redox status of the cell and mitochondrial stress responses to control life span.

R. M. Monaghan, R. G. Barnes, K. Fisher, T. Andreou, N. Rooney, G. B. Poulin, A. J. Whitmarsh, A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity. Nat. Cell Biol. 17, 782–792 (2015). [PubMed]