Mitochondrial Lon protease in human disease and aging: Including an etiologic classification of Lon-related diseases and disorders

Abstract

The Mitochondrial Lon protease, also called LonP1 is a product of the nuclear gene LONP1. Lon is a major regulator of mitochondrial metabolism and response to free radical damage, as well as an essential factor for the maintenance and repair of mitochondrial DNA. Lon is an ATP-stimulated protease that cycles between being bound (at the inner surface of the inner mitochondrial membrane) to the mitochondrial genome, and being released into the mitochondrial matrix where it can degrade matrix proteins. At least three different roles or functions have been ascribed to Lon: 1) Proteolytic digestion of oxidized proteins and the turnover of specific essential mitochondrial enzymes such as aconitase, TFAM, and StAR; 2) Mitochondrial (mt)DNA-binding protein, involved in mtDNA replication and mitogenesis; and 3) Protein chaperone, interacting with the Hsp60–mtHsp70 complex. LONP1 orthologs have been studied in bacteria, yeast, flies, worms, and mammals, evincing the widespread importance of the gene, as well as its remarkable evolutionary conservation. In recent years, we have witnessed a significant increase in knowledge regarding Lon's involvement in physiological functions, as well as in an expanding array of human disorders, including cancer, neurodegeneration, heart disease, and stroke. In addition, Lon appears to have a significant role in the aging process. A number of mitochondrial diseases have now been identified whose mechanisms involve various degrees of Lon dysfunction. In this paper we review current knowledge of Lon's function, under normal conditions, and we propose a new classification of human diseases characterized by a either over-expression or decline or loss of function of Lon. Lon has also been implicated in human aging, and we review the data currently available as well as speculating about possible interactions of aging and disease. Finally, we also discuss Lon as potential therapeutic target in human disease.

Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells

“…In healthy conditions, oxidized mitochondrial proteins are quickly removed via proteolytic degradation to prevent them from aggregating or cross-linking and resulting in cellular toxicity. LONM is a key enzyme involved in the elimination of oxidized proteins within the mitochondrial matrix which is crucial to maintaining cellular homeostasis (Ngo et al, 2013; Bota and Davies, 2016). It is also a key cytoprotective enzyme involved in aging and cellular response to oxidative stress/ hypoxia and the regulation of mitochondrial gene expression under such stress conditions (Ngo and Davies, 2009; Ngo et al, 2013; Bota and Davies, 2016; The consortium, U, 2017).…”

“…LONM is a key enzyme involved in the elimination of oxidized proteins within the mitochondrial matrix which is crucial to maintaining cellular homeostasis (Ngo et al, 2013; Bota and Davies, 2016). It is also a key cytoprotective enzyme involved in aging and cellular response to oxidative stress/ hypoxia and the regulation of mitochondrial gene expression under such stress conditions (Ngo and Davies, 2009; Ngo et al, 2013; Bota and Davies, 2016; The consortium, U, 2017). The loss of LONM responsiveness may contribute to the increased levels of protein damage, and mitochondrial dysfunction observed in aging and age-related diseases (Ngo and Davies, 2009; Ngo et al, 2013).…”

Introduction to Special Issue on Mitochondrial Redox Signaling in Health and Disease

“…The mitochondrial Lon protease is involved in several neurological disorders, such as hereditary Parkinson's disease, Friedreich ataxia, familial amyotrophic lateral sclerosis, brain ischemia and stroke [32]. In these disorders, the physiological functions of the Lon protease are altered: as a protease, as a chaperone,and as a mtDNA-binding protein [32].…”

“…In these disorders, the physiological functions of the Lon protease are altered: as a protease, as a chaperone,and as a mtDNA-binding protein [32].…”

Coordinating Mitochondrial Biology Through the Stress-Responsive Regulation of Mitochondrial Proteases

“…LON assembles as a homohexamer with each subunit containing both an AAA+ ATPase domain and a protected proteolytic core (Sauer and Baker, 2011). LON has a critical role in regulating mitochondrial matrix proteostasis through the degradation of oxidatively damaged and/or misfolded proteins such as aconitase (Bota and Davies, 2002, 2016; Bota et al, 2002). Furthermore, LON regulates many other aspects of mitochondrial function such as electron transport chain (ETC) activity, steroid synthesis, heme biosynthesis and mitochondrial transcription through the degradation of specific proteins such as the complex IV subunit COX4–1, steroid acute regulatory protein, and 5-aminolevulinic acid synthase, respectively (Fukuda et al, 2007; Granot et al, 2007; Matsushima et al, 2010; Quiros et al, 2014; Tian et al, 2011).…”