Monday, 9 March 2015

Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis

Ying Wang, Daniella Oxer and Siegfried Hekimi

Ubiquinone (UQ) is a central metabolite of the electron transport chain, accepting electrons from complexes I and II, and passing them to complex III. Using Cre-Lox recombination, the authors were able to knock out the enzyme which generates UQ (MCLK1) in adult mice after allowing them to develop normally, as conventional knock out of MCLK1 is embryonic lethal. Two weeks after the chemically-induced knock out, the mice had almost zero MCLK in all tested tissues, besides the liver which was unaffected.  

One might expect the mice to not survive much beyond the intervention, yet astonishingly the median survival was 276 days. UQ became depleted by as much as 90% over 6 months, in the most heavily affected tissues. Blood lactate levels were elevated, suggesting raised glycolysis. Respiratory rates in isolated tissues were reduced, but by no more that a factor of two. Respiratory enzyme activities were raised, likely in compensation for the low UQ availability.  8 months after treatment, the mice had almost zero UQ in heart tissue, and yet were still able to survive. This is particularly surprising, since the heart is such an energetically demanding tissue. Phenotypically, the animals tended to lose body fat, hair and generate a hunched posture. Further studies will be required to elucidate how such severe depletions in this metabolite can be withstood.

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