Related Experiment Video
Updated: Nov 15, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
The Mitochondrial Protease LonP1 Promotes Proteasome Inhibitor Resistance in Multiple Myeloma
Laure Maneix1,2,3,4, Melanie A Sweeney1,2,3,4, Sukyeong Lee5
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Multiple myeloma and its precursor plasma cell dyscrasias affect 3% of the elderly population in the US. Proteasome inhibitors are an essential part of several standard drug combinations used to treat this incurable cancer. These drugs interfere with the main pathway of protein degradation and lead to the accumulation of damaged proteins inside cells. Despite promising initial responses, multiple myeloma cells eventually become drug resistant in most patients. The biology behind relapsed/refractory multiple myeloma is complex and poorly understood. Several studies provide evidence that in addition to the proteasome, mitochondrial proteases can also contribute to protein quality control outside of mitochondria. We therefore hypothesized that mitochondrial proteases might counterbalance protein degradation in cancer cells treated with proteasome inhibitors. Using clinical and experimental data, we found that overexpression of the mitochondrial matrix protease LonP1 (Lon Peptidase 1) reduces the efficacy of proteasome inhibitors. Some proteasome inhibitors partially crossinhibit LonP1. However, we show that the resistance effect of LonP1 also occurs when using drugs that do not block this protease, suggesting that LonP1 can compensate for loss of proteasome activity. These results indicate that targeting both the proteasome and mitochondrial proteases such as LonP1 could be beneficial for treatment of multiple myeloma.
Insights
Multiple myeloma cells develop resistance to proteasome inhibitors by increasing mitochondrial protease LonP1 activity. Targeting both proteasome and LonP1 may improve treatment for this incurable cancer.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Multiple myeloma is an incurable cancer affecting 3% of the elderly population.
- Proteasome inhibitors are crucial in treating multiple myeloma but often lead to drug resistance.
- The mechanisms of relapsed/refractory multiple myeloma are complex and not fully understood.
Purpose of the Study:
- To investigate the role of mitochondrial proteases in counterbalancing proteasome inhibitor efficacy.
- To determine if mitochondrial proteases contribute to drug resistance in multiple myeloma.
Main Methods:
- Analysis of clinical and experimental data.
- Assessing the impact of LonP1 (Lon Peptidase 1) overexpression on proteasome inhibitor efficacy.
- Evaluating the cross-inhibition of LonP1 by certain proteasome inhibitors.
Main Results:
- Overexpression of mitochondrial matrix protease LonP1 reduces proteasome inhibitor efficacy.
- LonP1 overexpression confers resistance even to proteasome inhibitors that do not inhibit LonP1.
- LonP1 can compensate for proteasome activity loss.
Conclusions:
- Mitochondrial proteases, specifically LonP1, play a significant role in multiple myeloma drug resistance.
- Targeting both the proteasome and mitochondrial proteases like LonP1 could be a promising therapeutic strategy.
More Related Videos
Related Concept Videos
Mitochondrial Protein Sorting
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Mitochondrial Precursor Proteins
Most of the mitochondrial...
Abnormal Proliferation
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
The Proteasome
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...

