Multitasking in the mitochondrion by the ATP-dependent Lon protease

Venkatesh, Sundararajan; Lee, Jae; Singh, Kamalendra; Lee, Irene; Suzuki, Carolyn K.

doi:10.1016/j.bbamcr.2011.11.003

Cited by 148 publications

(142 citation statements)

References 133 publications

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“…This AAA + protease is involved in mitochondrial protein quality control. It degrades misfolded or oxidized proteins and acts as a chaperone in the assembly of protein complexes (56). We confirmed that LonP1 is induced under lipotoxic conditions in rat b-cells ( Supplementary Fig.…”

Section: Mitochondrial Dynamics and Quality Controlsupporting

confidence: 69%

RNA Sequencing Identifies Dysregulation of the Human Pancreatic Islet Transcriptome by the Saturated Fatty Acid Palmitate

et al. 2014

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Pancreatic b-cell dysfunction and death are central in the pathogenesis of type 2 diabetes (T2D). Saturated fatty acids cause b-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy, and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling b-cell phenotype, including PAX4 and GATA6. Fifty-nine T2D candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis of transcription factor binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA, and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced b-cell dysfunction and death. The data point to cross talk between metabolic stress and candidate genes at the b-cell level.

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Section: Mitochondrial Dynamics and Quality Controlsupporting

confidence: 69%

RNA Sequencing Identifies Dysregulation of the Human Pancreatic Islet Transcriptome by the Saturated Fatty Acid Palmitate

et al. 2014

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“…It has been suggested that Lon could be a viable anticancer drug target as drugs that inhibit Lon activity lead to cancer cell apoptosis in vitro either due to uncontrolled accumulation of misfolded proteins in general or due to the failure to control a specific regulator (48,51,52). General inhibitors of Lon activity, however, could cause potentially problematic pleiotropic side effects, and Lon defects have been associated with poor mitochondrial health and multiple human diseases (47,53,54). Thus, specific inhibitors that block proteolysis of key oncogenic substrates would be preferable and the SmiA precedent offers the potential for pathwayspecific antiadaptor therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…Eukaryotic Lon (37% identical to LonA of B. subtilis) (SI Appendix, Fig. S7) is involved in both the general degradation of misfolded proteins and in the specific remodeling of the mitochondrial proteins cytochrome C oxidase COX4-1, transcription factor A (TFAM), and the cholesterol regulator StAR (47)(48)(49)(50). It has been suggested that Lon could be a viable anticancer drug target as drugs that inhibit Lon activity lead to cancer cell apoptosis in vitro either due to uncontrolled accumulation of misfolded proteins in general or due to the failure to control a specific regulator (48,51,52).…”

Section: Discussionmentioning

confidence: 99%

Adaptor-mediated Lon proteolysis restrictsBacillus subtilishyperflagellation

Mukherjee

Bree

Liu

et al. 2014

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

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The Lon AAA+ protease is a highly conserved intracellular protease that is considered an anticancer target in eukaryotic cells and a crucial virulence regulator in bacteria. Lon degrades both damaged, misfolded proteins and specific native regulators, but how Lon discriminates among a large pool of candidate targets remains unclear. Here we report that Bacillus subtilis LonA specifically degrades the master regulator of flagellar biosynthesis SwrA governed by the adaptor protein swarming motility inhibitor A (SmiA). SmiA-dependent LonA proteolysis is abrogated upon microbe-substrate contact causing SwrA protein levels to increase and elevate flagellar density above a critical threshold for swarming motility atop solid surfaces. Surface contact-dependent cellular differentiation in bacteria is rapid, and regulated proteolysis may be a general mechanism of transducing surface stimuli.

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“…6 The ATP-dependent Lon protease is highly conserved from bacteria (La protease) to mammalian mitochondria and peroxisomes, and operates in protein quality control and stress response pathways by selectively degrading misfolded, misassembled, or damaged proteins. 7,8 Mitochondrial Lon supports cell viability during hypoxic, proteotoxic, and endoplasmic reticulum (ER) stress, [9][10][11] which are common stress phenotypes of cancer cells. During hypoxia, Lon is up-regulated by the hypoxia inducible factor-1␣ (HIF1-␣).…”

Section: Introductionmentioning

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

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130

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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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Multitasking in the mitochondrion by the ATP-dependent Lon protease

Cited by 148 publications

References 133 publications

RNA Sequencing Identifies Dysregulation of the Human Pancreatic Islet Transcriptome by the Saturated Fatty Acid Palmitate

RNA Sequencing Identifies Dysregulation of the Human Pancreatic Islet Transcriptome by the Saturated Fatty Acid Palmitate

Adaptor-mediated Lon proteolysis restrictsBacillus subtilishyperflagellation

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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