Fatigue Crack Arrest Induced by Localized Compressive Deformation.

The localized compressive deformation (LCD) effect generated by an indentation process at the crack tip on the fatigue crack growth of the 7075-T651 aluminum alloy is reported. Eccentrically loaded single-edge crack tension specimens (ESE(T)) were pre-cracked at a crack length of about 20 mm by applying a constant amplitude fatigue loading. Subsequently, the LCD process was performed by using a semi-spherical indenter with a radius of 16 mm to compress the crack tip zone at different forces (5.0, 7.0, 12.5, 13.5, 15.5 kN), applied on the opposite surfaces of the specimens. The fatigue cracking process was continued on the compressed samples until an overall crack length of about 30 mm was obtained. The compressive load and the number of delayed cycles is discussed in terms of crack length and crack tip opening displacement (CTOD). A direct relationship between the compressive force induced by the LCD process and the delay of the crack propagation due to the crack arrest was observed. This effect became evident at a compressive force of 5.0 kN, where the crack propagation was arrested for about 9000 cycles in comparison with the non-LCD sample. However, when the force increased, the crack arrest also increased. The crack was considered to be completely arrested at a compressive load of 15.5 kN, since the crack did not grow after the application of more than 3 × 106 cycles.

IDH2-mediated regulation of the biogenesis of the oxidative phosphorylation system.

Several subunits in the matrix domain of mitochondrial complex I (CI) have been posited to be redox sensors for CI, but how elevated levels of reactive oxygen species (ROS) impinge on CI assembly is unknown. We report that genetic disruption of the mitochondrial NADPH-generating enzyme, isocitrate dehydrogenase 2 (IDH2), in Drosophila flight muscles results in elevated ROS levels and impairment of assembly of the oxidative phosphorylation system (OXPHOS). Mechanistically, this begins with an inhibition of biosynthesis of the matrix domain of CI and progresses to involve multiple OXPHOS complexes. Despite activation of multiple compensatory mechanisms, including enhanced coenzyme Q biosynthesis and the mitochondrial unfolded protein response, ferroptotic cell death ensues. Disruption of enzymes that eliminate hydrogen peroxide, but not those that eliminate the superoxide radical, recapitulates the phenotype, thereby implicating hydrogen peroxide as the signaling molecule involved. Thus, IDH2 modulates the assembly of the matrix domain of CI and ultimately that of the entire OXPHOS.

Circadian regulation of mitochondrial uncoupling and lifespan.

Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, upregulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents overproliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target.