Lapointe et al. reveal that the partial depletion of a mitochondrial enzyme inhibits respiration by altering the distribution of the coenzyme ubiquinone (UQ).
The mitochondrial hydroxylase MCLK1 helps to synthesize UQ (also known as coenzyme Q), which transfers electrons along the respiratory chain of the mitochondrial inner membrane and also serves as an antioxidant there and in other cellular membranes. Though Mclk1-null mice die during embryogenesis, mice with a single copy of the Mclk1 gene live longer than wild-type animals, possibly because their metabolism is altered by a reduction in mitochondrial respiration. Yet UQ levels appear to be unchanged in Mclk1 heterozygotes, leaving it unclear why these animals have dysfunctional mitochondria.
Lapointe et al. found that, although the total amount of UQ was the same in mitochondria from Mclk1+/− and wild-type mice, the coenzyme’s distribution was altered in MCLK1-deficient animals so that UQ levels were higher than normal in the outer mitochondrial membrane and lower than normal in the inner membrane. Supplementing Mclk1+/− mice with extra dietary UQ restored inner membrane UQ levels and rescued electron transport.
Mice heterozygous for Coq3, another enzyme involved in UQ synthesis, showed no changes in the level or distribution of UQ or any alteration in mitochondrial function or lifespan. This suggests that MCLK1 is a limiting factor for UQ synthesis and that decreased inner membrane levels of the coenzyme compromise respiration and promote longevity. The paradoxical increase in outer membrane UQ in Mclk1+/− mice could be due to delayed turnover of the antioxidant molecule as a protective response against the oxidative stress caused by impaired respiratory chain function.
