LonP1 Differently Modulates Mitochondrial Function and Bioenergetics of Primary Versus Metastatic Colon Cancer Cells

Lara Gibellini,Anna Iannone,Simone Pecorini,Domenico Lo Tartaro,Francesco Mariani,Andrea Cossarizza,Luca Roncucci,Milena Nasi,Sara De Biasi,Paolo Pinton,Marcello Pinti,Lorena Losi,Anna De Gaetano,Alessandra Pisciotta,Simone Patergnani,Gianluca Carnevale

doi:10.3389/fonc.2018.00254

Abstract

Mitochondrial Lon protease (LonP1) is a multi-function enzyme that regulates mitochondrial functions in several human malignancies, including colorectal cancer (CRC). The mechanism(s) by which LonP1 contributes to colorectal carcinogenesis is not fully understood. We found that silencing LonP1 leads to severe mitochondrial impairment and apoptosis in colon cancer cells. Here, we investigate the role of LonP1 in mitochondrial functions, metabolism, and epithelial–mesenchymal transition (EMT) in colon tumor cells and in metastasis. LonP1 was almost absent in normal mucosa, gradually increased from aberrant crypt foci to adenoma, and was most abundant in CRC. Moreover, LonP1 was preferentially upregulated in colorectal samples with mutated p53 or nuclear β-catenin, and its overexpression led to increased levels of β-catenin and decreased levels of E-cadherin, key proteins in EMT, in vitro. LonP1 upregulation also induced opposite changes in oxidative phosphorylation, glycolysis, and pentose pathway in SW480 primary colon tumor cells when compared to SW620 metastatic colon cancer cells. In conclusion, basal LonP1 expression is essential for normal mitochondrial function, and increased LonP1 levels in SW480 and SW620 cells induce a metabolic shift toward glycolysis, leading to EMT.

Highlights

LonP1 is one of the main proteases patrolling the mitochondrial matrix
We show that elevated expression of LonP1 in colorectal cancer (CRC) tissues is associated with nuclear localization of βctn, and that overexpression of LonP1, in vitro, differently affects β-ctn expression in SW480 and SW620 colon cancer cells
We found that the LonP1 was almost absent in normal mucosa, gradually increased from samples of ACF to Ad, and was most abundant in samples of CRC (Figures 1A,B)

Summary

Introduction

LonP1 ( known as Lon or LonP) is one of the main proteases patrolling the mitochondrial matrix. Main targets of LonP1 proteolytic activity are: (i) folded proteins, including 5-aminolevulinic acid synthase, steroidogenic acute regulatory protein, mitochondrial transcription factor A, and cytochrome c oxidase 4 isoform 1; (ii) misfolded proteins, including glutaminase C; (iii) oxidized proteins, including aconitase and cystathionine β-synthase. Targets of LonP1 chaperone activity are still not known. More recent evidence suggests that LonP1 is responsible for additional functions critical to tumor progression, including metabolic adaptation to hypoxia, protection against senescence, and resistance to apoptosis and oxidative stress [11,12,13,14]. Recent data from our group demonstrated that LonP1 is upregulated in colorectal tumors, and that its downregulation or inhibition leads to severe mitochondrial dysfunction and to apoptosis [15, 16]

Methods

Results

Conclusion