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Mitochondrial Matrix Proteases As Novel Therapeutic Targets in Malignancy

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Mitochondrial Matrix Proteases As Novel Therapeutic Targets in Malignancy Oncogene (2014) 33, 2690–2699 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW Mitochondrial matrix proteases as novel therapeutic targets in malignancy CA Goard and AD Schimmer Although mitochondrial function is often altered in cancer, it remains essential for tumor viability. Tight control of protein homeostasis is required for the maintenance of mitochondrial function, and the mitochondrial matrix houses several coordinated protein quality control systems. These include three evolutionarily conserved proteases of the AAA þ superfamily—the Lon, ClpXP and m-AAA proteases. In humans, these proteases are proposed to degrade, process and chaperone the assembly of mitochondrial proteins in the matrix and inner membrane involved in oxidative phosphorylation, mitochondrial protein synthesis, mitochondrial network dynamics and nucleoid function. In addition, these proteases are upregulated by a variety of mitochondrial stressors, including oxidative stress, unfolded protein stress and imbalances in respiratory complex assembly. Given that tumor cells must survive and proliferate under dynamic cellular stress conditions, dysregulation of mitochondrial protein quality control systems may provide a selective advantage. The association of mitochondrial matrix AAA þ proteases with cancer and their potential for therapeutic modulation therefore warrant further consideration. Although our current knowledge of the endogenous human substrates of these proteases is limited, we highlight functional insights gained from cultured human cells, protease-deficient mouse models and other eukaryotic model organisms. We also review the consequences of disrupting mitochondrial matrix AAA þ proteases through genetic and pharmacological approaches, along with implications of these studies on the potential of these proteases as anticancer therapeutic targets. Oncogene (2014) 33, 2690–2699; doi:10.1038/onc.2013.228; published online 17 June 2013 Keywords: mitochondrial protease; m-AAA; ClpP; Lon; AAA þ ; protein quality control INTRODUCTION and may be therapeutically modulated with proteasome inhibitors The maintenance of protein homeostasis is critical for cell viability. such as the FDA-approved drug bortezomib,11 the impact of Proteins must be correctly folded, appropriately assembled into suppressing mitochondrial protein quality control in tumor cells is multimeric complexes and degraded when damaged or uncertain. Approximately 20 peptidases have been found unneeded. Eukaryotic cells possess several protein quality control throughout the different compartments of human mitochondria systems to refold, reassemble, degrade or sequester proteins, (that is, the outer mitochondrial membrane, intermembrane coordinated across distinct cellular compartments.1 The majority space, inner mitochondrial membrane and mitochondrial of nuclear, cytoplasmic and endoplasmic reticulum (ER) proteins matrix), including five major proteases involved in mitochondrial requiring removal or turnover are ubiquitylated and delivered to protein degradation.12,13 For example, the serine protease the 26S proteasome for degradation, whereas others are cleared HTRA2 (high temperature requirement A serine peptidase 2; also through autophagic delivery to lysosomes.1–4 In contrast to other known as OMI) is predominantly found in the mitochondrial cellular compartments and as a legacy of their endosymbiotic intermembrane space.14 HTRA2 is released from the mitochondria heritage, mitochondria maintain independent protein synthesis into the cytoplasm upon induction of apoptosis, where it can and degradation machinery. Mitochondria contain over 1000 mediate apoptotic and oncogenic signaling by cleaving substrates unique proteins encoded by the nuclear genome (nDNA), in such as inhibitor of apoptosis proteins (IAPs) and Wilms tumor addition to 13 proteins encoded by the small, circular, double- suppressor protein 1 (WT1).14–17 However, its physiological stranded mitochondrial genome (mtDNA) that are synthesized in function in the mitochondria is not fully understood.18,19 the mitochondrial matrix using distinct mitochondrial ribosomes The mitochondrial matrix contains three evolutionarily and translation machinery.5–7 These 13 proteins form subunits of conserved proteases of the ATPase associated with diverse cellular the respiratory chain complexes found in the inner mitochondrial activities þ (AAA þ ) superfamily—the Lon, caseinolytic peptidase membrane, assembling with 77 nDNA-encoded proteins to form XP (ClpXP) and matrix-oriented AAA (m-AAA) proteases five intact respiratory complexes arranged in an electron transport (Figure 1b).20 Each of these multimeric proteases are nDNA- chain for the aerobic generation of ATP through oxidative encoded and contain (i) a mitochondrial targeting sequence for phosphorylation (Figure 1a).8–10 import into the inner mitochondrial membrane or matrix, (ii) a Mitochondria also possess distinct protein quality control and conserved AAA þ superfamily ATPase module with classic Walker degradation systems. Although dysregulation of the ubiquitin- A and B motifs, and (iii) a protease domain. Together, these three proteasome system in the cytoplasm has been observed in cancer proteases coordinate the degradation, processing and assembly of Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada. Correspondence: Dr AD Schimmer, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, 610 University Avenue, Room 9-516, Toronto, Ontario, Canada M5G 2M9. E-mail: [email protected] Received 28 March 2013; revised 23 April 2013; accepted 30 April 2013; published online 17 June 2013 Mitochondrial matrix proteases as anticancer targets CA Goard and AD Schimmer 2691 ab OMM OMM Subunits nDNA: mtDNA: + H I 37 7 m-AAA Q II 4 0 H+ III 10 1 LONP1 C + mtDNA H IV 11 3 V H+ 15 2 ATP ClpXP IMM IMM Figure 1. Schematic representation of the mitochondrial oxidative phosphorylation and AAA þ protease systems. The mitochondrial matrix is separated from the cytoplasm by two membranes, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM). (a) Respiratory chain complexes I to V (where complex V is also known as the F1F0 ATP synthase) are found in the IMM and used to generate ATP in the mitochondrial matrix through oxidative phosphorylation. The numbers of subunits encoded by nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in mammalian mitochondria are listed. (b) The mitochondrial matrix contains three proteases of the AAA þ superfamily to modulate protein quality control and degradation. The human Lon protease, LONP1 (lon peptidase 1, mitochondrial), is found in both a free form and in association with mtDNA, which is assembled with several matrix proteins in a complex structure called the nucleoid. The human ClpXP protease is formed of the CLPP (ClpP caseinolytic peptidase, ATP-dependent, proteolytic subunit homolog (Escherichia coli)) protease in association with the CLPX (ClpX caseinolytic peptidase X homolog (E. coli)) ATPase. The matrix ATPase associated with diverse cellular activity (m-AAA) protease is tethered to the IMM, with its enzymatic domain exposed to the matrix. In humans, this protease can be formed as a heterooligomeric or homooligomeric complex of two subunit types. c, cytochrome c; Clp, caseinolytic peptidase; Q, coenzyme Q. Table 1. Human mitochondrial matrix AAA þ proteases and their homologs in major model organisms Homo sapiens Mus musculus Saccharomyces cerevisiae Escherichia coli Lon protease Lon protease Lon protease Lon protease LONP1 Lon Pim1p Lon (La) ClpXP protease ClpXP protease None a ClpXP protease CLPP ClpP ClpP CLPX ClpX ClpX m-AAA proteaseb m-AAA proteaseb m-AAA proteaseb FtsH AFG3L2 Afg3l2 Afg3p/Yta10p SPG7 Spg7 Rca1p/Yta12p Afg3l1 Abbreviations: Afg3, ATPase family gene 3; AFG3L2 and Afg3l2, AFG3 ATPase family gene 3-like 2 (S. cerevisiae); Afg3l1, AFG3 ATPase family gene 3-like 1 (S. cerevisiae); Clp, caseinolytic peptidase; CLPP and ClpP, ClpP caseinolytic peptidase, ATP-dependent, proteolytic subunit homolog (E. coli); CLPX and ClpX, ClpX caseinolytic peptidase X homolog (E. coli); FtsH, filamentous temperature-sensitive H; LONP1 and Lon, lon peptidase 1, mitochondrial; m-AAA, matrix ATPase associated with diverse cellular functions; Pim1, proteolysis in mitochondria; Rca1, respiratory chain assembly 1; Yta10 and Yta12, yeast tat-binding analog 10 and 12; SPG7 and Spg7, spastic paraplegia 7 (pure and complicated autosomal recessive). aAlthough S. cerevisiae does not harbor a homologous ClpXP protease complex or a CLPP homolog, it does encode a homolog of CLPX, Mcx1 (mitochondrial ClpX 1). bm-AAA composition has been observed as follows: in H. sapiens, homooligomers of AFG3L2 or heterooligomers of AFG3L2 and SPG7; in M. musculus, homooligomers of either Afg3l1 or Afg3l2 or heterooligomers of either of these proteins with Spg7; in S. cerevisiae, heteroologimers of Yta10p and Yta12p. proteins in the mitochondrial matrix and inner mitochondrial function has not yet been fully characterized, the human Lon membrane. This review provides an overview of the three protease—LONP1 (lon peptidase 1, mitochondrial; alternately mitochondrial matrix AAA þ proteases and assesses their roles denoted as LON or LONM)—appears to maintain mitochondrial as putative targets for novel anticancer therapeutics. Where matrix protein quality, regulate aerobic respiratory function, possible, known features
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