Mitochondrial Lon protease - depleted HeLa cells exhibit proteome modifications related to protein quality control, stress response and energy metabolism

Hamon, Marie-Paule; Gergondey, Rachel; L’honoré, Aurore; Friguet, Bertrand

doi:10.1016/j.freeradbiomed.2019.12.039

Cited by 6 publications

(5 citation statements)

References 82 publications

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“…This seemed to be counterintuitive since it would be expected that a lack of LONP1 may need to be compensated by an increased amount of CLPP. Indeed, analysis of a doxycycline-dependent LONP1 siRNA knock down showed an increase CLPP protein level ( 37 ). In the light of a reduced level of LONP1, a concomitant reduction of the potentially alternative protease CLPP would certainly represent a disadvantage for the cell, as CLPP and LONP1 may share some substrate proteins ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis demonstrates the role of the quality control protease LONP1 in mitochondrial protein aggregation

Pollecker

Sylvester

Voos

2021

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Proteomic analysis demonstrates the role of the quality control protease LONP1 in mitochondrial protein aggregation

Pollecker

Sylvester

Voos

2021

Journal of Biological Chemistry

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“…This suggests that complementary mechanisms are activated upon LonP1 disruption to combat mitochondrial stress. Indeed, LonP1 downregulation in HeLa cells was found to induce effects reminiscent of oxidative stress-related mitochondrial dysfunction, mainly through impairment of energy metabolic functions, such as the glycolytic and the respiratory capacity of mitochondria, and also to cause enhanced NRF2 expression and decreased cell proliferation [98]. However, siRNA-induced LonP1 disruption did not induce any of the above stress response pathways in WM266-4 metastatic melanoma cells, advocating in favor of the presence of additional compensatory mechanisms, owing to specific cellular demands.…”

Section: Discussionmentioning

confidence: 99%

Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease

Taouktsi

Kyriakou

Smyrniotis

et al. 2022

Cells

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Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPRmt and UPRcyt) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPRcyt responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPRmt and UPRcyt pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging.

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“…This seemed to be counterintuitive since it would be expected that a lack of LONP1 may need to be compensated by an increased amount of CLPP. Indeed, analysis of a doxycycline-dependent LONP1 siRNA knock down showed, not surprisingly, an increase CLPP protein level (42). In the light of a reduced level of LONP1, a concomitant reduction of the potentially alternative protease CLPP would certainly represent a disadvantage for the cell, as CLPP and LONP1 share some substrate proteins, including oxidative phosphorylation, TCA cycle, amino acid and lipid metabolism (43).…”

Section: Effects Of Reduced Lonp1 Protein Levelsmentioning

confidence: 99%

Proteomic analysis of the role of the quality control protease LONP1 in mitochondrial protein aggregation

Pollecker

Sylvester

Voos

2021

Preprint

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The mitochondrial matrix protease LONP1 is an essential part of the organellar protein quality control system. LONP1 has been shown to be involved in respiration control and apoptosis. Furthermore, a reduction in LONP1 level correlates with ageing processes. Up to now, the effects of a LONP1 defect were mostly studied by utilizing transient, siRNA-mediated knockdown approaches. We generated a new cellular model system for studying the impact of LONP1 on mitochondrial protein homeostasis by a CRISPR/Cas-mediated genetic knockdown (gKD). These cells show a stable reduction of LONP1 along with a mild phenotype characterized by absent morphological differences and only small negative effects on mitochondrial functions under normal culture conditions. To assess the consequences of a permanent LONP1 depletion on the mitochondrial proteome, we analyzed the alterations of protein levels by quantitative mass spectroscopy, demonstrating small adaptive changes, in particular concerning mitochondrial protein biogenesis. In an additional proteomic analysis, we determined the temperature-dependent aggregation behavior of mitochondrial proteins and its dependence on a reduction of LONP1 activity, demonstrating the important role of the protease for mitochondrial protein homeostasis in mammalian cells. We identified a significant number of new mitochondrial proteins that are affected by LONP1 activity concerning their stress-induced solubility. Taken together, our results suggest a very good applicability of the LONP1 gKD cell line as a model system for human ageing processes.

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Mitochondrial Lon protease - depleted HeLa cells exhibit proteome modifications related to protein quality control, stress response and energy metabolism

Cited by 6 publications

References 82 publications

Proteomic analysis demonstrates the role of the quality control protease LONP1 in mitochondrial protein aggregation

Proteomic analysis demonstrates the role of the quality control protease LONP1 in mitochondrial protein aggregation

Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease

Proteomic analysis of the role of the quality control protease LONP1 in mitochondrial protein aggregation

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