Identification of Novel Oxidized Protein Substrates and Physiological Partners of the Mitochondrial ATP-dependent Lon-like Protease Pim1

Bayot, Aurélien; Gareil, Monique; Rogowska-Wrzesińska, Adelina; Roepstorff, Peter; Friguet, Bertrand; Bulteau, Anne‐Laure

doi:10.1074/jbc.m109.065425

Cited by 89 publications

(83 citation statements)

References 75 publications

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“…To test whether Pim1 activity per se is altered in cells defective in Fe-S cluster biogenesis, we assessed the level of a known Pim1 substrate, the ribosomal protein Mrs20 (20). Although Mrp20 levels were increased in Δpim1 cells, as expected, they were not increased in Δssq1 cells (Fig.…”

Section: Resultsmentioning

confidence: 72%

Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold

Song

Marszałek

Craig

2012

Proc. Natl. Acad. Sci. U.S.A.

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Fe-S clusters are critical prosthetic groups for proteins involved in various critical biological processes. Before being transferred to recipient apo-proteins, Fe-S clusters are assembled on the highly conserved scaffold protein Isu, the abundance of which is regulated posttranslationally on disruption of the cluster biogenesis system. Here we report that Isu is degraded by the Lon-type AAA+ ATPase protease of the mitochondrial matrix, Pim1. Nfs1, the cysteine desulfurase responsible for providing sulfur for cluster formation, is required for the increased Isu stability occurring after disruption of cluster formation on or transfer from Isu. Physical interaction between the Isu and Nfs1 proteins, not the enzymatic activity of Nfs1, is the important factor in increased stability. Analysis of several conditions revealed that high Isu levels can be advantageous or disadvantageous, depending on the physiological condition. During the stationary phase, elevated Isu levels were advantageous, resulting in prolonged chronological lifespan. On the other hand, under iron-limiting conditions, high Isu levels were deleterious. Compared with cells expressing normal levels of Isu, such cells grew poorly and exhibited reduced activity of the heme-containing enzyme ferric reductase. Our results suggest that modulation of the degradation of Isu by the Pim1 protease is a regulatory mechanism serving to rapidly help balance the cell's need for critical ironrequiring processes under changing environmental conditions. proteolysis | Hsp70 | aging | Saccharomyces cerevisiae

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Section: Resultsmentioning

confidence: 72%

Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold

Song

Marszałek

Craig

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The protease responsible for degrading oxidatively damaged matrix proteins in yeast (Bayot et al, 2010;Bender et al, 2011) and mammalian mitochondria (Bota and Davies, 2002) is the ATP-dependent Lon protease. However, recent studies in Arabidopsis indicate the mitochondrial LON1 protease to be nonessential for the turnover of oxidized proteins (Solheim et al, 2012).…”

Section: In Ftsh4 the Defective Oxphos System Is Linked To Enhanced mentioning

confidence: 99%

Lack of FTSH4 Protease Affects Protein Carbonylation, Mitochondrial Morphology, and Phospholipid Content in Mitochondria of Arabidopsis: New Insights into a Complex Interplay

et al. 2016

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FTSH4 is one of the inner membrane-embedded ATP-dependent metalloproteases in mitochondria of Arabidopsis (Arabidopsis thaliana). In mutants impaired to express FTSH4, carbonylated proteins accumulated and leaf morphology was altered when grown under a short-day photoperiod, at 22°C, and a long-day photoperiod, at 30°C. To provide better insight into the function of FTSH4, we compared the mitochondrial proteomes and oxyproteomes of two ftsh4 mutants and wild-type plants grown under conditions inducing the phenotypic alterations. Numerous proteins from various submitochondrial compartments were observed to be carbonylated in the ftsh4 mutants, indicating a widespread oxidative stress. One of the reasons for the accumulation of carbonylated proteins in ftsh4 was the limited ATP-dependent proteolytic capacity of ftsh4 mitochondria, arising from insufficient ATP amount, probably as a result of an impaired oxidative phosphorylation (OXPHOS), especially complex V. In ftsh4, we further observed giant, spherical mitochondria coexisting among normal ones. Both effects, the increased number of abnormal mitochondria and the decreased stability/activity of the OXPHOS complexes, were probably caused by the lower amount of the mitochondrial membrane phospholipid cardiolipin. We postulate that the reduced cardiolipin content in ftsh4 mitochondria leads to perturbations within the OXPHOS complexes, generating more reactive oxygen species and less ATP, and to the deregulation of mitochondrial dynamics, causing in consequence the accumulation of oxidative damage.

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Section: Introductionmentioning

confidence: 99%

“…In addition, Lon has been shown to specifically degrade mildly oxidized proteins within mitochondria. [13][14][15] Thus, the up-regulation of Lon may be critical for cancer cell survival by preventing mitochondrial proteotoxicity elicited by oxidative, hypoxic, and ER stress.The synthetic oleanane triterpenoids (SOs) such as 2-cyano-3, 12-dioxooleana-1,9-dien-28-oic acid (CDDO), are multifunctional electrophilic agents that in a dose-dependent manner are either antitumorigenic, anti-inflammatory, or cytoprotective. 16 The proposed mechanism underlying the anticancer effects of SOs is by the formation of Michael adducts between SOs and reactive nucleophiles, such as free thiols on target proteins.…”

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confidence: 99%

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

Bernstein

Venkatesh

et al. 2012

Blood

130

125

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Synthetic triterpenoids are multitarget compounds exhibiting promise as preventative and therapeutic agents for cancer. Their proposed mechanism of action is by forming Michael adducts with reactive nucleophilic groups on target proteins. Our previous work demonstrates that the 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives promote B-lymphoid cell apoptosis through a mitochondria-mediated pathway linked to mitochondrial protein aggregation. As one function of the Lon protease is to eliminate abnormal mitochondrial proteins, we hypothesized that CDDO-induced protein aggregation and lymphoma apoptosis occur by inactivating this enzyme. Here, we show that CDDO and its derivatives directly and selectively inhibit Lon. CDDO blocks Lon-mediated proteolysis in biochemical and cellular assays, but does not inhibit the 20S proteasome. Furthermore, a biotinylated-CDDO conjugate modifies mitochondrial Lon. A striking common phenotype of CDDO-treated lymphoma cells and Lon-knockdown cells is the accumulation of electron-dense aggregates within mitochondria. We also show that Lon protein levels are substantially elevated in malignant lymphoma cells, compared with resting or activated B cells. Finally, we demonstrate that Lon knockdown leads to lymphoma cell death. Together, these findings suggest that Lon inhibition plays a contributory role in CDDO-induced lymphoma cell death, and support the concept that mitochondrial Lon is a novel anticancer drug target. IntroductionThe malignant transformation of normal cells into cancer cells is driven principally by enhanced oncogenic protein function and/or inactivation of tumor suppressors. To promote this transformation process, tumor cells undergo an extensive reprogramming of normal growth and survival pathways that are mediated by nononcogenic proteins. The identification of nononcogenic proteins that are essential for the survival and proliferation of cancer cells provides potential new drug targets for anticancer therapeutics. Nononcogenic proteins participating in the cell stress response have emerged as a unique and important class of viable targets. Recent work demonstrates that pharmacologic inhibition or downregulation of the master transcriptional regulator of the cell stress response-heat shock factor 1 (HSF1), 1 as well as of the molecular chaperones HSP70 or HSP90, selectively inhibit tumor development. 2,3 Remarkably, the inhibition or down-regulation of these essential heat-shock response proteins effectively limits cancer cell growth without substantially compromising normal cell survival. 1,2,4 Luo and colleagues 6 have expanded on the classic hallmarks of cancer originally proposed by Hanahan and Weinberg 5 to include several common stress phenotypes of tumorigenesis. The neoplastic transformation of cancer cells gives rise to diverse oncogenic stressors such as DNA damage and mitotic stress, as well as to metabolic, proteotoxic, and oxidative stress. Cancer cells thus depend on conserved defense mechanisms to survive such oncogenic str...

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Identification of Novel Oxidized Protein Substrates and Physiological Partners of the Mitochondrial ATP-dependent Lon-like Protease Pim1

Cited by 89 publications

References 75 publications

Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold

Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold

Lack of FTSH4 Protease Affects Protein Carbonylation, Mitochondrial Morphology, and Phospholipid Content in Mitochondria of Arabidopsis: New Insights into a Complex Interplay

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

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