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

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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.

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Abbreviations

AAA+:

ATPase associated with diverse cellular activities

Aco2:

Aconitase 2

ALAS-1:

5-aminolevulinic acid synthase 1

AOX:

acyl-CoA oxidase

cART:

Combined antiretroviral therapy

C/EBP:

CCAAT-enhancer-binding protein

CBS:

Cystathionine β-synthase

CDDO-Me:

2-cyano-3, 12-dioxoo- leana-1,9(11)-dien-28-oic methyl ester

CDDO:

2-cyano-3, 12-dioxoo- leana-1,9(11)-dien-28-oic acid

CHOP:

C/EBP homology protein

Clp:

Caseinolytic protease

ClpX:

Caseinolytic protease X

cLβL:

Clasto-lactacystin β-lactone

CODAS:

Cerebral, ocular, dental, auricular and skeletal anomalies

COX:

Cytochrome c oxidase

COX4-1:

Cytochrome c oxidase, subunit 4, isoform 1

CR:

Caloric restriction

EMT:

Epithelial–mesenchymal transition

ER:

Endoplasmic reticulum

ERK1:

Extracellular-signal-regulated kinase 1

ERK2:

Extracellular-signal-regulated kinase 2

FITC:

Fluorescein isothiocyanate

GLS-1:

Glutaminase C

HIF1-α:

Hypoxia inducible factor 1 α

HIV:

Human immunodeficiency virus

JNK:

c-Jun N-terminal kinase

LONP1:

Lon peptidase 1, mitochondrial

Lyf-1:

Lymphoid transcription factor

m-AAA:

Matrix-ATPase associated with diverse cellular activities

MELAS:

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

MERRF:

Myoclonic epilepsy with ragged-red fibre

MMP-2:

Matrix metalloproteinase-2

MnSOD:

Manganese superoxide dismutase

mtDNA:

Mitochondrial DNA

MTS:

Mitochondrial-targeting sequence

NDFUS3:

NADH dehydrogenase (ubiquinone) Fe-S protein 3

NDFUS7:

NADH dehydrogenase (ubiquinone) Fe-S protein 7

NDFUS8:

NADH dehydrogenase (ubiquinone) Fe-S protein 8

NDUFB6:

NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6

NDUFV1:

NADH dehydrogenase (ubiquinone) flavoprotein 1

NDUFV2:

NADH dehydrogenase (ubiquinone) flavoprotein 2

NF-kB:

Nuclear factor kappa-B

Nkx2-5:

NK2 homeobox 5

NRF1:

Nuclear respiratory factor 1

NRF2:

Nuclear respiratory factor 2

NRTI:

Nucleotide analogue reverse transcriptase inhibitor

OA:

Obtusilactone A

OCR:

Oxygen consumption rate

OXPHOS:

Oxidative phosphorylation

PGC1 α:

Peroxisome proliferator-activated receptor γ coactivator 1 α

Pim1:

Proteolysis into mitochondria 1

PMP70:

70-kDa peroxisomal membrane protein

PMSF:

Phenylmethanesulphonylfluoride

POLDIP2:

Polymerase (DNA-directed) delta interacting protein 2

PRSS15:

Serine protease 15

PI:

Protease inhibitor

PTS1:

Peroxisomal targeting sequence type-1

ROS:

Reactive oxygen species

SDH:

Succinate dehydrogenase

SDH5:

Succinate dehydrogenase 5

SDHA:

Succinate dehydrogenase complex, subunit A

SIRT1:

Sirtuin 1

SIRT3:

Sirtuin 3

StAR:

Steroidogenic acute regulatory protein

TCA cycle:

Tricarboxylic acid cycle

TFAM:

Mitochondrial transcription factor A

Tysnd1:

Trypsin domain containing 1

VHL:

Von Hippel Lindau tumour suppressor

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Acknowledgments

This study has been supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Grant No. 11341 to AC, and by grants from the National Basic Research Program of China (973 Program, No. 2013CB531700), National Natural Science Foundation of China (No. 31070710, No. 31171345), Zhejiang Qianjiang Talent Project B (No. 2010R10045) to BL.

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  1. Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi, 287, 41125, Modena, Italy

    Marcello Pinti

  2. Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Lara Gibellini & Andrea Cossarizza

  3. School of Life Sciences, Institute of Biophysics, Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Yongzhang Liu, Shan Xu & Bin Lu

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  1. Marcello Pinti
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  2. Lara Gibellini
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Correspondence to Marcello Pinti.

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Pinti, M., Gibellini, L., Liu, Y. et al. Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer. Cell. Mol. Life Sci. 72, 4807–4824 (2015). https://doi.org/10.1007/s00018-015-2039-3

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