title: Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity.
abstract: 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 insulin-stimulated 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 γ-coactivator 1-α (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.
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX78245, USA.
authors.forename: Sathyaseelan S
authors.initials: SS
authors.lastname: Deepa
authors.forename: Daniel
authors.initials: D
authors.lastname: Pulliam
authors.forename: Shauna
authors.initials: S
authors.lastname: Hill
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.forename: Michael E
authors.initials: ME
authors.lastname: Walsh
authors.forename: Adam
authors.initials: A
authors.lastname: Salmon
authors.forename: Lauren
authors.initials: L
authors.lastname: Sloane
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D047495:PPAR gamma; C092928:Surf-1 protein; D003576:Electron Transport Complex IV; D011972:Receptor, Insulin