Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer

Abstract

Lon protease is a nuclear DNA-encoded mitochondrial enzyme highly conserved throughout evolution, involved in the degradation of damaged and oxidized proteins of the mitochondrial matrix, in the correct folding of proteins imported in mitochondria, and in the maintenance of mitochondrial DNA. Lon expression is induced by various stimuli, including hypoxia and reactive oxygen species, and provides protection against cell stress. Lon down-regulation is associated with ageing and with cell senescence, while up-regulation is observed in tumour cells, and is correlated with a more aggressive phenotype of cancer. Lon up-regulation contributes to metabolic reprogramming observed in cancer, favours the switch from a respiratory to a glycolytic metabolism, helping cancer cell survival in the tumour microenvironment, and contributes to epithelial to mesenchymal transition. Silencing of Lon, or pharmacological inhibition of its activity, causes cell death in various cancer cells. Thus, Lon can be included in the growing class of proteins that are not responsible for oncogenic transformation, but that are essential for survival and proliferation of cancer cells, and that can be considered as a new target for development of anticancer drugs.

The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress

“…The protein sequencing data indicates that both 60kD and 50kD Lon protein isoforms correspond to the central region of the primary 100kD Lon, suggesting that Lon may be cleaved at both amino and carboxyl ends. Moreover, the female-specific 50kD isoform might have a regulatory or chaperone-like role, as Lon has been previously shown to regulate assembly of protein complexes in the mitochondria and to bind to mitochondrial DNA, independent of function as a protease [39]. …”

Posttranslational control of the scaffold for Fe–S cluster biogenesis as a compensatory regulatory mechanism

“…1). Employing Pim1 dependent degradation of Isu fits well with the emerging appreciation of a more profound role of Lon-like proteases in regulation of mitochondrial physiology, in addition to their well established quality control function (Quiros et al 2014; Pinti et al 2015, 2016). In the case of Isu regulation, binding of Nfs1 to Isu diminishes its susceptibility to Pim1 degradation, while concurrently initiating the first step of Fe–S cluster biogenesis.…”

The Protease Locus of Francisella tularensis LVS Is Required for Stress Tolerance and Infection in the Mammalian Host

“…Lon has been implicated in controlling mitochondrial matrix protein quality, regulating aerobic respiratory function, degrading oxidized proteins, and maintaining mitochondrial DNA (mtDNA) nucleoid integrity (73). Dysfunction of human LONP1 has been associated with ageing, cancer, and CODAS syndrome, a multisystem developmental disorder in humans (73,74).…”