Upregulation of the mitochondrial Lon Protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging

The elimination of oxidatively modified proteins is a crucial process in maintaining cellular homeostasis, especially during stress. Mitochondria are protein-dense, high traffic compartments, whose polypeptides are constantly exposed to superoxide, hydrogen peroxide, and other reactive species, generated by ‘electron leakage’ from the respiratory chain. The level of oxidative stress to mitochondrial proteins is not constant, but instead varies greatly with numerous metabolic and environmental factors. Oxidized mitochondrial proteins must be removed rapidly (by proteolytic degradation) or they will aggregate, cross-link, and cause toxicity. The Lon Protease is a key enzyme in the degradation of oxidized proteins within the mitochondrial matrix. Under conditions of acute stress Lon is highly inducible, possibly with the oxidant acting as the signal inducer, thereby providing increased protection. It seems that under chronic stress conditions, however, Lon levels actually decline. Lon levels also decline with age and with senescence, and senescent cells even lose the ability to induce Lon during acute stress. We propose that the regulation of Lon is biphasic, in that it is up-regulated during transient stress and down-regulated during chronic stress and aging, and we suggest that the loss of Lon responsiveness may be a significant factor in aging, and in age-related diseases

Sex-specific adaptive homeostasis in D. melanogaster depends on increased proteolysis by the 20S Proteasome: Data-in-Brief

Adaptive homeostasis enables rapid cellular signaling, leading to transcriptional and translational modifications (Davies, 2016) [1]. The Proteasome is one of the main cellular proteolytic enzymes that plays an essential role in the rapid clearance of oxidatively damaged cellular proteins, and is highly responsive to oxidative stress. Upon exposure to even very low, signaling levels of oxidants, the predominant form of the Proteasome becomes the ATP-independent 20S proteasome that enables rapid clearance of damaged proteins. Subsequently there is also a concurrent upregulation of de novo 20S proteasome synthesis. These cellular adaptations not only ensure effective and efficient removal of damaged proteins, but prepare cells to better cope with future, more severe oxidative insults. Male and female Drosophila melanogaster fruit flies were pretreated with an adaptive amount of an oxidant (10 µM hydrogen peroxide or 0.5 µM paraquat) to assess the changes in proteolytic capacity and the role of the 20S proteasome. Additionally, the adaptive signaling by non-damaging amounts of hydrogen peroxide or paraquat) were used to assess changes in male and female fruit flies, following a subsequent more toxic amount of the two oxidants. Further analysis and detailed results about the adaptive role of the 20S proteasome in multiple D. melanogaster strains can be found in “Sexual Dimorphism in Oxidant-Induced Adaptive Homeostasis in Multiple Wild-Type D. melanogaster Strains” (Pomatto et al., 2018) [2]. Keywords: 20S proteasome, Sexual-dimorphism, Adaptive homeostasis, Proteolysis, D. melanogaste