Lon-dependent proteolysis in oxidative stress responses

Abstract

Accumulation of reactive oxygen species (ROS) induces oxidative stress, leading to substantial damage to cellular macromolecules, necessitating efficient protein quality control mechanisms. The Lon protease, a highly conserved ATP-dependent protease, is thought to play a central role in mitigating oxidative stress by targeting damaged and misfolded proteins for degradation. This review examines the role of Lon in oxidative stress responses, including its role in degrading oxidized proteins, regulating antioxidant pathways, and modulating heme and Fe-S cluster homeostasis. We highlight cases of substrate recognition through structural changes and describe situations where Lon activity is further regulated by redox conditions. By synthesizing studies across a range of organisms, we find that despite the clear importance of Lon for oxidative stress tolerance, universal rules for Lon degradation of damaged proteins during this response remain unclear.

Keywords: AAA+ protease; Lon; bacteria; carbonylation; iron homeostasis; mitochondria; oxidative stress; quality control; redox.

Fig 1

Overview of oxidative damage on macromolecules (DNA, lipids, and proteins) and the role of Lon protease in cellular defense against oxidative stress. Protective roles of Lon protease include regulation of oxidative stress responses (21, 22) and potential removal of oxidatively damaged proteins (8, 23–25).

Fig 2

Organisms where Lon is involved in the defense against oxidative stress. Lon is important for maintaining mitochondrial ROS levels in Drosophila melanogaster and HeLa cells (62, 63), the survival of Actinobacillus pleuropneumoniae during oxidative stress likely arises from phagocytosis by macrophages (64), and the viability of Sordaria macrospora, Brucella abortus, Caulobacter crescentus, and Salmonella typhimurium during oxidative stress induced by H₂O₂ (65–67).

Fig 3

Cartoon depiction of Lon protease activation by oxidation in E. coli and by reduction in mice. Exposure of E. coli Lon to air or glutathione disulfide (GSSG) triggers the formation of an intrachain disulfide bond, which enlarges the exit pore and accelerates proteolysis (80). In contrast, Lon protease activity in aging mouse models decreases due to oxidation but can be restored through reduction (81).

Fig 4

Known oxidized substrates of Lon protease in several different species. Lon degrades oxidatively damaged forms of peroxisomal catalase of Penicillium chrysogenum (88), PerR of B. subtilis (22), and mitochondrial aconitase of humans, yeast (S. cerevisiae), and fungus (Podospora anserina) (23, 76, 89).