Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity

Mice lacking Surf1, a complex IV assembly protein, have 50-70% reduction in cytochrome c oxidase activity in all tissues yet a paradoxical increase in lifespan. Here we report that Surf1^-/- mice have lower body (15%) and fat (20%) mass, in association with reduced lipid storage, smaller adipocytes, and elevated indicators of fatty acid oxidation in white adipose tissue (WAT) compared with control mice. The respiratory quotient in the Surf1^-/- mice was significantly lower than in the control animals (0.83- 0.93 vs. 0.90-0.98), consistent with enhanced fat utilization in Surf1^-/- mice. Elevated fat utilization was associated with increased insulin sensitivity measured as insulinstimulated glucose uptake, as well as an increase in insulin receptor levels (2-fold) and glucose transporter type 4 (GLUT4; 1.3-fold) levels in WAT in the Surf1^-/- mice. The expression of peroxisome proliferator- activated receptor β-coactivator 1 (PGC-1α) mRNA and protein was up-regulated by 2.5- and 1.9- fold, respectively, in WAT from Surf1^-/- mice, and the expression of PGC-1α target genes and markers of mitochondrial biogenesis was elevated. Together, these findings point to a novel and unexpected link between reduced mitochondrial complex IV activity, enhanced insulin sensitivity, and increased mitochondrial biogenesis that may contribute to the increased longevity in the Surf1^-/- mice.-Deepa, S. S., Pulliam, D., Hill, S., Shi, Y., Walsh, M. E., Salmon, A., Sloane, L., Zhang, N., Zeviani, M., Viscomi, C., Musi, N., Van Remmen, H. Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity. FASEB J. 27, 1371-1380 (2013). www.fasebj.org.