JOURNAL OF HAZARDOUS MATERIALS
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2025
·
IF 11.3
Wei Yang,Yu Li,Ruzhen Feng,Peiyao Liang,Kefan Tian,Lingli Hu,Kejing Wang,Tianming Qiu,Jingyuan Zhang,Xiance Sun,Xiaofeng Yao
Perfluorooctane sulfonate (PFOS), a listed persistent organic pollutant, poses risks to human health and is closely linked to chronic metabolic diseases. Although the role of mitochondrial fission in these diseases has garnered attention, whether and how PFOS induces mitochondrial fission remains obscure. Here, we found that PFOS induced mitochondrial fission, as demonstrated by the fragmentation of mitochondria and the upregulation of dynamin-related protein 1 (DRP1), phospho-DRP1 and mitochondrial fission protein 1 (FIS1) in human hepatocytes MIHA and mice liver. Blocking the calcium transfer from lysosomes to mitochondria that was executed by transient receptor potential mucolipin 1 (TRPML1) of lysosomes and voltage-dependent anion channel 1 (VDAC1) of mitochondria, did not affect PFOS-induced mitochondrial fission. In contrast, knockdown of TRPML1 or VDAC1 reversed this process. Knockdown of mitochondrial calcium uniporter (MCU), rather than inhibiting its activity, effectively alleviated PFOS-induced mitochondrial fission. Additionally, PFOS increased MCU oligomers without affecting MCU monomer. Inhibiting autophagy reversed the MCU oligomerization. Further investigation unveiled the interactions of MCU with VDAC1, TRPML1, mitochondrial Fo complex subunit F2 (ATP5J2) and DRP1 in PFOS-exposed mice liver and MIHA cells. We also discovered that knockdown of ATP5J2 alleviated PFOS-induced mitochondrial fission. Ulteriorly, PFOS upregulated ATP5J2 that underwent oligomerization. Knockdown of MCU reversed the increase in ATP5J2. Our study uncovers the presence and molecular basics of lysosomes-regulated mitochondrial fission under PFOS exposure, explains the regulatory pathways on MCU and ATP5J2 oligomerization and their pivotal roles in mitochondrial fission, highlighting the involvement of mitochondrial fission in PFOS-related health risks.
研究领域:
细胞生物学
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毒理学
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代谢疾病研究
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2024
·Vol. 10
·期 1
·1-12
·
IF 6.1
Fan Chunhong,Wu Haotian,Du Xin,Li Canjun,Zeng Wenping,Qu Lili,Cang Chunlei
Cancer stem cells (CSCs) are a sub-population of cells possessing high tumorigenic potential, which contribute to therapeutic resistance, metastasis and recurrence. Eradication of CSCs is widely recognized as a crucial factor in improving patient prognosis, yet the effective targeting of these cells remains a major challenge. Here, we show that the lysosomal cation channel TRPML1 represents a promising target for CSCs. TRPML1 is highly expressed in breast cancer cells and exhibits sensitivity to salinomycin, a drug known to selectively eliminate CSCs. Pharmacological inhibition and genetic depletion of TRPML1 promote ferroptosis in breast CSCs, reduce their stemness, and enhance the sensitivity of breast cancer cells to chemotherapy drug doxorubicin. The inhibition and knockout of TRPML1 also demonstrate significant suppression of tumor formation and growth in the mouse xenograft model. These findings suggest that targeting TRPML1 to eliminate CSCs may be an effective strategy for the treatment of breast cancer.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2024
·
IF 3.5
Dai Meifang,Lin Bingqian,Li Hao,Wang Youming,Wu Miaomiao,Wei Yanan,Zeng Wenping,Qu Lili,Cang Chunlei,Wang Xingbing
Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid leukemia (AML). Notably, the involvement of lysosomes in chemoresistance has sparked interest in developing lysosome-targeted therapies to sensitize tumor cells to currently approved chemotherapy or as innovative pharmacological approaches. Moreover, as ion channels on the lysosomal membrane are critical regulators of lysosomal function, they present potential as novel targets for enhancing chemosensitivity. Here, we discovered that the expression of a lysosomal cation channel, namely transient receptor potential mucolipin 1 (TRPML1), was elevated in AML cells. Inhibiting TRPML1 individually does not impact the proliferation and apoptosis of AML cells. Importantly, inhibition of TRPML1 demonstrated the potential to modulate the sensitivity of AML cells to chemotherapeutic agents. Exploration of the underlying mechanisms revealed that suppression of TRPML1 impaired autophagy while concurrently increasing the production of reactive oxygen species (ROS) and ROS-mediated lipid peroxidation (Lipid-ROS) in AML cells. Finally, the knockdown of TRPML1 significantly reduced OCI-AML3 tumor growth following chemotherapy in a mouse model of human leukemia. In summary, targeting TRPML1 represents a promising approach for combination therapy aimed at enhancing chemosensitivity in treating AML.
研究领域:
肿瘤学
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细胞生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
One Health Advances
·
2026
·Vol. 4
·期 1
·32
·
IF 5
Ni Baihai,Du Jiayu,Li Zimeng,Jian Pingan,Chen Mingshan,Li Jinlong,Li Xuenan
One common plasticizer is di(2-ethylhexyl) phthalate (DEHP). We use it a lot in our daily lives, and prolonged exposure to it can be harmful to living things. One form of selective autophagy that can break down damaged lysosomes is called lysophagy. Conversely, excessive occurrence of lysophagy can in turn cause lysosomal damage. Here, we show that DEHP stimulates the transient receptor potential mucoLipin 1-transcription factor EB (TRPML1-TFEB) pathway, drives excessive lysophagy, resulting in lysosomal dysfunction and kidney injury in mice. One carotenoid with strong antioxidant qualities is lycopene (LYC). It is frequently employed to offset the effects of DEHP. Interestingly, our results showed that LYC can reduce kidney damage caused by DEHP in mice. Inhibiting the TRPML1-TFEB pathway's activation and reducing lysophagy are two of the mechanisms of action. In summary, LYC significantly alleviates DEHP-induced injury in mouse renal tubular epithelial cells by inhibiting TRPML1-TFEB pathway-mediated lysophagy. LYC successfully reduced the damage caused by mono(2-ethylhexyl) phthalate in human renal proximal tubular epithelial cells, confirming this effect in vitro. This study establishes a critical link between LYC treatment and lysophagy as well as lysosomal dysfunction in DEHP-induced mouse renal tubular epithelial cells. This study offers novel mechanistic perspectives on DEHP-induced nephrotoxicity and the renal protection conferred by LYC. Graphical
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DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
·
IF 6.2
Jixun Li,Ruzhen Feng,Wei Yang,Peiyao Liang,Tianming Qiu,Jingyuan Zhang,Xiance Sun,Qiujuan Li,Guang Yang,Xiaofeng Yao
Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5–24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.
研究领域:
毒理学
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细胞生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
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