Monday, 27 March 2017

Dynamin-Related Protein 1-Dependent Mitochondrial Fission Changes in the Dorsal Vagal Complex Regulate Insulin Action

Beatrice M. Filippi, Mona A. Abraham, Pamuditha N. Silva, Mozhgan Rasti, Mary P. LaPierre, Paige V. Bauer, Jonathan V. Rocheleau, Tony K.T. Lam
Type 2 diabetes is a condition where the body does not produce enough, or is resistant to, insulin. In this study, the authors investigated the role mitochondrial dynamics plays in insulin resistance and glucose regulation. As well as its clinical consequences, this study offers to shed light on the relationship between glucose homeostasis and mitochondrial functionality.
In healthy rodents, the hypothalamus and dorsal vagal complex (DVC) regulate glucose homeostasis in the liver (which is where excess glucose is stored). However, after a high fat diet (HFD) as short as 3 days, this regulation is disrupted. This link between the DVC and high-fat feeding has been poorly understood. 
The authors found that, after a HFD, DVC neuronal cells in rats had a higher density of mitochondria, and these mitochondria were less elongated, shorter and less branched. 
The authors tested the effect of providing the 3-day HFD rats with an infusion of  MDIVI-1, which is an inhibitor of the mitochondrial fission factor Drp-1 (by blocking its translocation from the cytosol into the mitochondria). The authors found that, upon infusion, mitochondrial morphology was restored to wild-type levels, the glucose infusion rate increased to normal levels, as well as the glucose production rate decreasing to normal levels. This was confirmed through molecular inhibition of Drp-1 via adenoviral-mediated inhibition. Furthermore, inducing overexpression of Drp-1 in the DVC of rats which were fed normally induced insulin resistance and recapitulated the effects of HFD.

The authors found that endoplasmic reticulum (ER) stress was necessary and sufficient  to induce DVC-mediated insulin resistance, and that ER stress was a consequence of mitochondrial fission.

Thoughts: Are these associations still observed on a long-term high-fat diet, rather than a 3-day alteration to diet?

Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU

Paillard M, Csordás G, Szanda G, Golenár T, Debattisti V, Bartok A, Wang N, Moffat C, Seifert EL, Spät A, Hajnóczky G

Mitochondrial respiration is sensitive to the concentration of calcium in the cytoplasm, acting as an important control mechanism of respiration rate. It is known that different tissues have different responses to the presence of calcium. For instance, in the liver, calcium oscillations in the cytoplasm tend to be low frequency and are effectively propagated to intra-mitochondrial calcium concentrations. However, in the heart, oscillations are high frequency and are integrated into a more continuous intra-mitochondrial calcium signal.

Here, the authors investigated the difference in mitochondrial response to calcium concentration in different tissues by measuring the relative stoichiometry of two protein components of the mitochondrial calcium uniporter: MCU (a calcium pore unit) and MICU1 (a Calcium-sensing regulator). The authors found that, in heart tissue, a low MICU1 to MCU ratio is present, which results in a low cytoplasmic calcium threshold for mitochondrial accumulation of calcium, relative to liver tissue. Furthermore, heart tissue displayed a more shallow response curve to cytoplasmic calcium, suggesting lower cooperativity in cardiac tissue, relative to liver tissue. Therefore, the ratio of MICU1:MCU controls the tissue-specific response to cytoplasmic calcium.