Early Mitochondrial Dysfunction in Long-lived Mclk1+/- Mice

We show that 2-fold reduction of MCLK1 expression in mice reveals an additional function for the protein, as this level of reduction does not affect ubiquinone levels yet affects mitochondrial function substantially

Jérôme Lapointe; Siegfried Hekimi


Scholarcy highlights

  • Porter of the mitochondrial respiratory chain
  • Reduction in Mitochondrial Electron Transport between Mitochondrial Complexes Despite Normal Levels of Ubiquinone—We have shown previously that Mclk1ϩ/Ϫ tissues exhibit the expected 2-fold decrease in Mclk1 mRNA and MCLK1 protein levels but that UQ9 levels were unaffected in tissue homogenates from such mice
  • As we have found that the heterozygous mice have an extended lifespan, and for other reasons outlined in the introduction, there are grounds to believe that CLK-1/ MCLK1 could have an additional activity unrelated to UQ biosynthesis but responsible for the phenotypes observed in Mclk1ϩ/Ϫ heterozygous mutants
  • Our study strongly suggests that CLK-1/MCLK1 determines lifespan in a ubiquinone-independent manner
  • We had found that UQ levels were reduced in the livers of very old, moribund, Mclk1ϩ/Ϫ mutants but not in young animals due to the presence in the former of cells that had lost both copies of Mclk1 by loss-of-heterozygosity
  • The levels of 8-hydroxy-2-deoxyguanosine appear slightly reduced in Mclk1ϩ/Ϫ animals, we found no significant difference between genotypes
  • Our conclusion of a second function for CLK1/MCLK1 is consistent with a recent study which indicates that exogenous CoQ10 is unable to restore wild-type ATP levels in dissociated cells from Mclk1Ϫ/Ϫ embryos cultured in vitro
  • Low levels of total NAD should negatively affect the activity of extra-mitochondrial NADH/NADPH oxidases, which are known to be major generators of ROS and, contribute to reduce the accumulation of systemic oxidative damage that is likely involved in the increased lifespan phenotype of the Mclk1ϩ/Ϫ mice

Need more features? Save interactive summary cards to your Scholarcy Library.