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Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal
Yinong Wang1, Bingzhi Wang2, Yu Liu1
1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Glutamine addiction is a key metabolic vulnerability in cancer. However, the mechanisms governing the limited efficacy of glutamine metabolism inhibitor (GMI) monotherapy require further investigation. Via single-cell monitoring using a caspase-3 activity indicator, we identified SLC25A6 as a key mediator of GMI-induced apoptosis in colorectal cancer cells. SLC25A6 overexpression enhanced apoptosis both in vitro and in vivo. SLC25A6 promoted mitochondrial fragmentation and dysfunction and upregulated the expression of mitochondrial fission markers. Notably, mitofission inhibitors largely abolished SLC25A6-related mitochondrial dysfunction and intrinsic apoptosis. Mechanistically, SLC25A6 directly interacted with MIC60, competitively inhibiting MIC19 binding; both MIC60 and MIC19 are key components of the mitochondrial contact site and cristae organizing system (MICOS). The SLC25A6 T126A mutant failed to bind MIC60 and lost its ability to destabilize the MICOS complex and facilitate mitofission. Upregulation of SLC25A6 expression induced by the glutaminase inhibitor CB-839 sensitized cancer cells to the Bcl-2 inhibitor ABT-199. Combined CB-839 and ABT-199 treatment showed strong synergistic antitumor effects in colorectal cancer xenograft models. Our findings reveal a novel function of SLC25A6 that links metabolic stress to mitochondrial apoptosis via disruption of the MICOS complex. Combination treatments with mitochondrial apoptotic inducers represent a promising avenue for maximizing the efficacy of GMIs in cancer treatment.
Insights
Glutamine metabolism inhibitors (GMIs) show limited efficacy. Researchers found SLC25A6 mediates GMI-induced apoptosis by disrupting the mitochondrial MICOS complex, enhancing cancer cell death. Combination therapy shows promise.
Area of Science:
- Oncology
- Cancer Metabolism
- Mitochondrial Biology
Background:
- Cancer cells rely on glutamine metabolism, presenting a therapeutic vulnerability.
- Glutamine metabolism inhibitor (GMI) monotherapy has limited efficacy due to unelucidated mechanisms.
- Understanding resistance mechanisms is crucial for improving cancer treatment strategies.
Purpose of the Study:
- To identify key mediators of GMI-induced apoptosis in colorectal cancer.
- To elucidate the molecular mechanisms linking glutamine metabolism to cancer cell death.
- To explore combination therapies for enhanced anti-cancer effects.
Main Methods:
- Single-cell monitoring using caspase-3 activity indicator.
- Investigated the role of SLC25A6 in GMI-induced apoptosis.
- Utilized in vitro and in vivo colorectal cancer models.
- Analyzed mitochondrial function, fragmentation, and MICOS complex interactions.
- Tested combination therapy with CB-839 (glutaminase inhibitor) and ABT-199 (Bcl-2 inhibitor).
Main Results:
- SLC25A6 was identified as a key mediator of GMI-induced apoptosis.
- SLC25A6 overexpression enhanced apoptosis and promoted mitochondrial fragmentation and dysfunction.
- SLC25A6 directly interacted with MIC60, disrupting the MICOS complex and facilitating mitofission.
- CB-839 induced SLC25A6 upregulation, sensitizing cells to ABT-199.
- Combined CB-839 and ABT-199 demonstrated synergistic anti-tumor effects in vivo.
Conclusions:
- SLC25A6 links metabolic stress to mitochondrial apoptosis by disrupting the MICOS complex.
- Targeting SLC25A6 and combining GMIs with mitochondrial apoptotic inducers offers a promising strategy to overcome GMI resistance.
- This research provides a novel therapeutic avenue for colorectal cancer treatment.
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