Abstract
Insulin/insulin-like growth factor signalling (IIS), acting primarily through the PI3-kinase (PI3K)/AKT kinase signalling cassette, plays key evolutionarily conserved regulatory roles in nutrient homeostasis, growth, ageing and longevity. The dysfunction of this pathway has been linked to several age-related human diseases including cancer, Type 2 diabetes and neurodegenerative disorders. However, it remains unclear whether minor defects in IIS can independently induce the age-dependent functional decline in cells that accompany some of these diseases or whether IIS alters the sensitivity to other aberrant signalling. We identified a novel hypomorphic allele of PI3K’s direct antagonist, Phosphatase and tensin homologue on chromosome 10 (Pten), in the fruit fly, Drosophila melanogaster. Adults carrying combinations of this allele, Pten 5, combined with strong loss-of-function Pten mutations exhibit subtle or no increase in mass, but are highly susceptible to a wide range of stresses. They also exhibit dramatic upregulation of the oxidative stress response gene, GstD1, and a progressive loss of motor function that ultimately leads to defects in climbing and flight ability. The latter phenotype is associated with mitochondrial disruption in indirect flight muscles, although overall muscle structure appears to be maintained. We show that the phenotype is partially rescued by muscle-specific expression of the Bcl-2 homologue Buffy, which in flies, maintains mitochondrial integrity, modulates energy homeostasis and suppresses cell death. The flightless phenotype is also suppressed by mutations in downstream IIS signalling components, including those in the mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway, suggesting that elevated IIS is responsible for functional decline in flight muscle. Our data demonstrate that IIS levels must be precisely regulated by Pten in adults to maintain the function of the highly metabolically active indirect flight muscles, offering a new system to study the in vivo roles of IIS in the maintenance of mitochondrial integrity and adult ageing.
Highlights
The insulin/insulin-like growth factor signalling (IIS) cascade and one of its major target pathways involving the nutrient-sensitive kinase complex mechanistic Target of Rapamycin Complex 1 (mTORC1) play key evolutionarily conserved roles in nutrient homeostasis, cell growth regulation, autophagy and longevity [1]
Pten1 has not been molecularly characterised, while Ptendj189 contains an F-element insertion in the Phosphatase and tensin homologue on chromosome 10 (Pten) coding sequence after amino acid 89, which should remove the phosphatase domain of the protein
We describe a new hypomorphic viable recessive mutation in the IIS antagonist Pten, which is associated with increased stress sensitivity, a progressive adult flightless phenotype and severe mitochondrial disruption within the indirect flight muscles in aging flies
Summary
The insulin/insulin-like growth factor signalling (IIS) cascade and one of its major target pathways involving the nutrient-sensitive kinase complex mTORC1 (mechanistic Target of Rapamycin Complex 1) play key evolutionarily conserved roles in nutrient homeostasis, cell growth regulation, autophagy and longevity [1]. The dysfunction of these pathways is associated with several human diseases including diabetes, cancer and neurodegenerative disorders, though in the latter case, the mechanisms involved have not been fully elucidated. The IIS-regulated cellular changes that modulate functional decline of tissues like nerve and muscle during ageing are not fully understood
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