Enhanced mitochondrial biogenesis is associated with increased expression of the mitochondrial ATP‐dependent Lon protease

Luciaková, Katarína; Sokolikova, Barbora; Chloupkova, Maria; Nelson, Bruce R.

doi:10.1016/s0014-5793(99)00058-7

Cited by 43 publications

(34 citation statements)

References 33 publications

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“…44 In addition, Lon is overexpressed in rat Zajdela hepatoma tumor cells. 45 Our findings strongly suggest that Lon is a physiologic target of CDDO, and the first specific mitochondrial protein target of this compound to be identified. We demonstrate that CDDO and its derivatives selectively and directly block the protease activity of Lon.…”

Section: Discussionmentioning

confidence: 58%

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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Section: Discussionmentioning

confidence: 58%

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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“…They also contain a proteolytic system able to recognise and selectively degrade oxidatively modified proteins [203,204], thus defending against the accumulation of oxidized proteins. Evidence shows that the expression of a mitochondrial matrix protease, the Lon protease, which may play a key role in this important process [205], is enhanced by thyroid hormone [206]. These results suggest that thyroid hormone is able to carry out a double action on mitochondrial proteins.…”

Section: Turnover Of Mitochondrial Proteinsmentioning

confidence: 99%

Thyroid hormone-induced oxidative stress

Venditti

Meo

2006

Cell. Mol. Life Sci.

345

230

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Hypermetabolic state in hyperthyroidism is associated with tissue oxidative injury. Available data indicate that hyperthyroid tissues exhibit an increased ROS and RNS production. The increased mitochondrial ROS generation is a side effect of the enhanced level of electron carriers, by which hyperthyroid tissues increase their metabolic capacity. Investigations of antioxidant defence system have returned controversial results. Moreover, other thyroid hormone-linked biochemical changes increase tissue susceptibility to oxidative challenge, which exacerbates the injury and dysfunction they suffer under stressful conditions. Mitochondria, as a primary target for oxidative stress, might account for hyperthyroidism linked tissue dysfunction. This is consistent with the inverse relationship found between functional recovery of ischemic hyperthyroid hearts and mitochondrial oxidative damage and respiration impairment. However, thyroid hormone-activated mitochondrial mechanisms provide protection against excessive tissue dysfunction, including increased expression of uncoupling proteins, proteolytic enzymes and transcriptional coactivator PGC-1, and stimulate opening of permeability transition pores.

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“…Indeed, in the absence of Pim1, yeast becomes respiratorydeficient because it is unable to maintain mDNA, leading to accumulatin of electron-dense inclusion bodies in the mitochondrial matrix [12]. Finally, in humans, lon protease is associated with mitochondrial biogenesis; lon protease deficiency is responsible for the abnormal structure of mitochondria [13,14].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells

et al. 2011

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Aims/hypothesis Lon protease degrades oxidatively damaged proteins in mitochondrial matrix. To examine the relationships between mitochondrial quality control, mitochondrial functions and diabetes, we investigated whether lon protease deficiency influences insulin resistance by affecting mitochondrial function. Methods Lon protease-specific small interfering RNA (siRNA) was transfected into human liver SK-HEP-1 cells and changes in molecules related to insulin resistance were analysed. Results Reduction in lon protease was achieved using specific siRNA-induced mitochondrial dysfunction in human liver SK-HEP-1 cells. Concurrently, insulin signalling and subsequent insulin action were impaired and levels of gluconeogenic enzymes were increased by lon protein deficiency. Moreover, the activity of mitogen-activated protein kinases and transcription factors related to hepatic gluconeogenesis were elevated in LON (also known as LONP1) siRNA-transfected cells via increased intracellular reactive oxygen species production. Overproduction of lon protease restored mitochondrial function and also diminished the insulin resistance induced by treatment with cholesterol and palmitate. In addition, levels of lon protease decreased dramatically in livers of diabetic db/db mice compared with their lean mice counterparts. Conclusions/interpretationHere we have demonstrated that reduction of lon protease induced hepatic insulin resistance by lowering mitochondrial function. This is the first study to report that defects in mitochondrial protein quality control could cause insulin resistance and diabetes.

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Enhanced mitochondrial biogenesis is associated with increased expression of the mitochondrial ATP‐dependent Lon protease

Cited by 43 publications

References 33 publications

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

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

Thyroid hormone-induced oxidative stress

Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells

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