Developmental Programming of Mitochondrial Function Limits Lifespan in Short-Lived Animals

Abstract

The contribution of mitochondria to lifespan determination remains controversial, as impaired mitochondrial function can paradoxically both shorten and extend longevity. During ageing, mitochondria accumulate defects that disrupt electron transport and elevate the production of reactive oxygen species (ROS) per unit of ATP. Here, we developed Drosophila melanogaster models carrying mitochondria that phenocopy aged organelles--termed "aged-like" mitochondria--to dissect the developmental versus adult contributions of mitochondrial dysfunction to lifespan regulation. Inducing aged-like mitochondria during development caused profound metabolic maladaptation and markedly reduced adult lifespan, without signs of accelerated ageing. In contrast, restricting their expression to adulthood resulted in only a modest reduction in lifespan, accompanied by an increased mortality rate, indicative of accelerated ageing. Enhancing mitochondrial function exclusively during development by expressing the alternative oxidase (AOX) mitigated these metabolic defects and significantly extended adult survival. Likewise, developmental overexpression of Rheb, an activator of Target of Rapamycin (TOR) signalling, improved adult survival without restoring mitochondrial respiration. Finally, we show that mitochondrial respiratory capacity cannot be reinstated in adults with "aged-like" mitochondria, as oxidative phosphorylation (OXPHOS) protein levels are largely established during development and remain stable throughout adult life. We propose that Drosophila permanently tunes adult metabolism according to developmental cues to optimise reproductive fitness, at the expense of long-term survival.