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Mitochondrial LINC00942 activates complex I and inhibits ferroptosis through interacting with GRSF1 in liver cancer
Yina Liao1, Yue Su1, Yanfang Liu1
1Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Abstract:
Emerging evidence suggests that long non-coding RNAs (lncRNAs) play crucial roles in ferroptosis regulation, yet the detailed mechanisms remain largely elusive. In this study, we identify LINC00942, a ferroptosis-associated lncRNA, which localizes to mitochondria and coordinates ferroptosis and tumorigenesis by modulating mitochondrial function. Bioinformatic analysis establishes that LINC00942 is specifically overexpressed in hepatocellular carcinoma (HCC), and its high expression is closely associated with poor patient prognosis. Both in vitro and in vivo experiments demonstrate that LINC00942 promotes HCC cell proliferation, migration, and invasion. Furthermore, suppression of LINC00942 disrupts mitochondrial function, impairs energy metabolism, and increases mitochondrial lipid peroxidation and reactive oxygen species (ROS) levels, rendering HCC cells more susceptible to ferroptosis. Mechanistically, LINC00942 interacts with G-rich sequence factor 1 (GRSF1) and subsequently translocates to the mitochondria. Within mitochondria, LINC00942 facilitates the binding of GRSF1 to complex I mRNA, thereby enhancing the translation efficiency of complex I subunits. The resulting upregulation of complex I protein levels strengthens its enzymatic activity and promotes mitochondrial oxidative phosphorylation, while concurrently suppressing ferroptosis. In addition, DNA demethylation and CREB1 contribute to the transcriptional activation of LINC00942 in HCC. Notably, administration of GalNAc-conjugated siRNA targeting LINC00942 effectively suppresses tumor growth in orthotopic xenograft models. Collectively, these findings underscore the oncogenic function of LINC00942 through the modulation of mitochondrial bioenergetics and ferroptosis, highlighting it as a promising therapeutic target for HCC.
Insights
Long non-coding RNA LINC00942 promotes hepatocellular carcinoma (HCC) by disrupting mitochondrial function and suppressing ferroptosis. Targeting LINC00942 with siRNA offers a potential therapeutic strategy for HCC treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Mitochondrial Biology
Background:
- Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in cellular processes.
- The precise mechanisms by which lncRNAs regulate ferroptosis, a form of programmed cell death, are not fully understood.
- Hepatocellular carcinoma (HCC) pathogenesis involves complex molecular events, including dysregulation of cell death pathways.
Purpose of the Study:
- To identify and characterize the role of LINC00942 in hepatocellular carcinoma (HCC).
- To elucidate the molecular mechanisms by which LINC00942 influences ferroptosis and tumorigenesis.
- To evaluate LINC00942 as a potential therapeutic target for HCC.
Main Methods:
- Bioinformatic analysis of LINC00942 expression in HCC patient data.
- In vitro and in vivo experiments to assess the functional impact of LINC00942 on HCC cells.
- Mitochondrial function assays, including assessment of oxidative phosphorylation and reactive oxygen species (ROS) levels.
- RNA immunoprecipitation and Western blotting to investigate LINC00942-GRSF1 interaction and Complex I expression.
- Assessment of tumor growth inhibition using GalNAc-conjugated siRNA in orthotopic xenograft models.
Main Results:
- LINC00942 is overexpressed in HCC and associated with poor prognosis.
- LINC00942 promotes HCC cell proliferation, migration, and invasion.
- LINC00942 knockdown impairs mitochondrial function, increases lipid peroxidation and ROS, sensitizing cells to ferroptosis.
- LINC00942 interacts with GRSF1, enhancing Complex I translation and mitochondrial oxidative phosphorylation, thereby suppressing ferroptosis.
- Transcriptional activation of LINC00942 involves DNA demethylation and CREB1.
- Targeting LINC00942 with siRNA suppressed tumor growth in vivo.
Conclusions:
- LINC00942 acts as an oncogene in HCC by modulating mitochondrial bioenergetics and ferroptosis.
- The LINC00942/GRSF1 axis is critical for maintaining mitochondrial function and inhibiting ferroptosis in HCC.
- LINC00942 represents a promising therapeutic target for HCC treatment.
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