The peroxisomal Lon protease LonP2 in aging and disease: functions and comparisons with mitochondrial Lon protease LonP1

Abstract

Peroxisomes are ubiquitous eukaryotic organelles with the primary role of breaking down very long- and branched-chain fatty acids for subsequent β-oxidation in the mitochondrion. Like mitochondria, peroxisomes are major sites for oxygen utilization and potential contributors to cellular oxidative stress. The accumulation of oxidatively damaged proteins, which often develop into inclusion bodies (of oxidized, aggregated, and cross-linked proteins) within both mitochondria and peroxisomes, results in loss of organelle function that may contribute to the aging process. Both organelles possess an isoform of the Lon protease that is responsible for degrading proteins damaged by oxidation. While the importance of mitochondrial Lon (LonP1) in relation to oxidative stress and aging has been established, little is known regarding the role of LonP2 and aging-related changes in the peroxisome. Recently, peroxisome dysfunction has been associated with aging-related diseases indicating that peroxisome maintenance is a critical component of 'healthy aging'. Although mitochondria and peroxisomes are both needed for fatty acid metabolism, little work has focused on understanding the relationship between these two organelles including how age-dependent changes in one organelle may be detrimental for the other. Herein, we summarize findings that establish proteolytic degradation of damaged proteins by the Lon protease as a vital mechanism to maintain protein homeostasis within the peroxisome. Due to the metabolic coordination between peroxisomes and mitochondria, understanding the role of Lon in the aging peroxisome may help to elucidate cellular causes for both peroxisome and mitochondrial dysfunction.

Keywords: Lon protease; aging; chaperone; hormesis; mitochondria; mitochondrial DNA; oxidative stress; peroxisome; reactive oxygen species.

Fig. 1

Sources of superoxide, hydrogen peroxide, nitric oxide radical, peroxynitrite, and hydroxyl radical production in the peroxisome. Hydrogen peroxide (H₂O₂) is the main metabolic by-product of fatty acid metabolism in peroxisomes. The primary oxidase to carry out the direct generation of H₂O₂ is acyl CoA oxidase (Foerster et al., 1981). In addition, superoxide (O₂^{• −}), a by-product of the breakdown of xanthine, is scavenged by copper-zinc superoxide dismutase (CuZn SOD) and converted into H₂O₂ and O₂ (Foerster et al., 1981). The majority of H₂O₂ produced in the peroxisome is degraded by catalase and glutathione peroxidase. The remainder may undergo Fenton chemistry, resulting in the formation of the hydroxyl radical (^•OH). In addition, a portion of H₂O₂ is leaked into the cytoplasm, where it is reduced by glutathione peroxidase (Halliwell & Gutteridge, 1989). Breakdown of amino acids may generate the nitric oxide radical (NO^•) which reacts rapidly with O₂^{• −} to generate peroxynitrite (ONOO⁻).

Fig. 2

Peroxisomal and mitochondrial Lon protease. (A) The sequence alignment between the mitochondrial (LonP1) and peroxisomal (LonP2) forms of Lon. Identical sequences are shown in red and similar sequences are shown in grey. (B, C) Conserved domains of the P2 peroxisome-specific (B) and P1 mitochondrion-specific (C) isoforms of Lon. Both LonP1 and LonP2 contain a substrate recognition, ‘N’ domain to bind oxidized proteins. Both isoforms possess a classical ATPase domain containing Walker (A) and (B) motifs that have a characteristic tertiary structure commonly found in ATP-binding proteins. Lastly, both contain a proteolytic domain that relies upon a catalytically active serine residue for substrate degradation. However, unlike LonP1, which has a mitochondrial targeting sequence on the N-terminus, LonP2 relies upon the peroxisomal targeting sequence, which consists of a conserved three amino acid SRL motif.

Fig. 3

The Lon protease and aging-related changes. (A, C) During periods of acute oxidative stress, peroxisomes and mitochondria quickly adapt to the oxidative insult by up-regulating LonP1 and LonP2. (A) In young mitochondria, the resulting increase in proteolytic activity of LonP1 ensures rapid degradation of damaged proteins and maintenance of homeostasis. (B) Young peroxisomes adapt to changes in metabolic demand by rapidly increasing the breakdown of odd-chain fatty acids for increased acetyl-CoA production, which consequently fuels mitochondrial energy production. To compensate for the excess generation of hydrogen peroxide, up-regulation of LonP2 counteracts the increased peroxisome-dependent protein damage. (B, D) Senescent cells that are exposed to chronic oxidative stress lose ability to degrade oxidized organelle proteins. (B) In aged mitochondria, the ability to rapidly up-regulate LonP1 declines, leading to the accumulation of protein aggregates, and eventual loss of mitochondrial function. (D) In peroxisomes, a similar phenomenon may occur, in which the decreased ability to elevate LonP2 levels rapidly could also lead to protein aggregation and the gradual loss of peroxisome function.