bims-mecosi 2023-10-08 papers

Issue of 2023‒10‒08
five papers selected by
Verena Kohler, Umeå University

Commun Biol. 2023 Oct 04. 6(1): 1008

Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites.

Nina Criado Santos, Samuel Bouvet, Maria Cruz Cobo, Marion Mandavit, Flavien Bermont, Cyril Castelbou, Farah Mansour, Maral Azam, Francesca Giordano, Paula Nunes-Hasler.

Phagosome maturation is critical for immune defense, defining whether ingested material is destroyed or converted into antigens. Sec22b regulates phagosome maturation, yet how has remained unclear. Here we show Sec22b tethers endoplasmic reticulum-phagosome membrane contact sites (MCS) independently of the known tether STIM1. Sec22b knockdown increases calcium signaling, phagolysosome fusion and antigen degradation and alters phagosomal phospholipids PI(3)P, PS and PI(4)P. Levels of PI(4)P, a lysosome docking lipid, are rescued by Sec22b re-expression and by expression of the artificial tether MAPPER but not the MCS-disrupting mutant Sec22b-P33. Moreover, Sec22b co-precipitates with the PS/PI(4)P exchange protein ORP8. Wild-type, but not mutant ORP8 rescues phagosomal PI(4)P and reduces antigen degradation. Sec22b, MAPPER and ORP8 but not P33 or mutant-ORP8 restores phagolysosome fusion in knockdown cells. These findings clarify an alternative mechanism through which Sec22b controls phagosome maturation and beg a reassessment of the relative contribution of Sec22b-mediated fusion versus tethering to phagosome biology.

DOI: https://doi.org/10.1038/s42003-023-05382-0

bioRxiv. 2023 Sep 18. pii: 2023.09.18.557036. [Epub ahead of print]

The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites.

Pia Hempelmann, Fabio Lolicato, Andrea Graziadei, Ryan D R Brown, Sarah Spiegel, Juri Rappsilber, Walter Nickel, Doris Höglinger, Denisa Jamecna.

Sphingolipids are important structural components of membranes. Additionally, simple sphingolipids such as sphingosine are highly bioactive and participate in complex subcellular signaling. Sphingolipid deregulation is associated with many severe diseases including diabetes, Parkinson's and cancer. Here, we focus on how sphingosine, generated from sphingolipid catabolism in late endosomes/lysosomes, is reintegrated into the biosynthetic machinery at the endoplasmic reticulum (ER). We characterized the sterol transporter STARD3 as a sphingosine transporter acting at lysosome-ER contact sites. Experiments featuring crosslinkable sphingosine probes, supported by unbiased molecular dynamics simulations, exposed how sphingosine binds to the lipid-binding domain of STARD3. Following the metabolic fate of pre-localized lysosomal sphingosine showed the importance of STARD3 and its actions at contact sites for the integration of sphingosine into ceramide in a cellular context. Our findings provide the first example of inter-organellar sphingosine transfer and pave the way for a better understanding of sphingolipid - sterol co-regulation.

DOI: https://doi.org/10.1101/2023.09.18.557036

Int J Biol Sci. 2023 ;19(14): 4427-4441

Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease.

Yong Liu, Yingjin Qiao, Shaokang Pan, Jingfang Chen, Zihui Mao, Kaidi Ren, Yang Yang, Qi Feng, Dongwei Liu, Zhangsuo Liu.

Diabetic kidney disease (DKD) is a global health issue that presents a complex pathogenesis and limited treatment options. To provide guidance for precise therapies, it is crucial to accurately identify the pathogenesis of DKD. Several studies have recognized that mitochondrial and endoplasmic reticulum (ER) dysfunction are key drivers of the pathogenesis of DKD. The mitochondria-associated ER membrane (MAM) is a dynamic membrane contact site (MSC) that connects the ER and mitochondria and is essential in maintaining the normal function of the two organelles. MAM is involved in various cellular processes, including lipid synthesis and transport, calcium homeostasis, mitochondrial fusion and fission, and ER stress. Meanwhile, recent studies confirm that MAM plays a significant role in the pathogenesis of DKD by regulating glucose metabolism, lipid metabolism, inflammation, ER stress, mitochondrial fission and fusion, and autophagy. Herein, this review aims to provide a comprehensive summary of the physiological function of MAMs and their impact on the progression of DKD. Subsequently, we discuss the trend of pharmaceutical studies that target MAM resident proteins for treating DKD. Furthermore, we also explore the future development prospects of MAM in DKD research, thereby providing a new perspective for basic studies and clinical treatment of DKD.

Keywords: Mitochondria-associated endoplasmic reticulum membrane (MAM); calcium homeostasis; diabetic kidney disease (DKD); lipid metabolism; mitochondrial physiology

DOI: https://doi.org/10.7150/ijbs.86608

Fungal Biol Rev. 2023 Mar;pii: 100286. [Epub ahead of print]43

Heme sensing and trafficking in fungi.

Peng Xue, Eddy Sánchez-León, Djihane Damoo, Guanggan Hu, Won Hee Jung, James W Kronstad.

Fungal pathogens cause life-threatening diseases in humans, and the increasing prevalence of these diseases emphasizes the need for new targets for therapeutic intervention. Nutrient acquisition during infection is a promising target, and recent studies highlight the contributions of endomembrane trafficking, mitochondria, and vacuoles in the sensing and acquisition of heme by fungi. These studies have been facilitated by genetically encoded biosensors and other tools to quantitate heme in subcellular compartments and to investigate the dynamics of trafficking in living cells. In particular, the applications of biosensors in fungi have been extended beyond the detection of metabolites, cofactors, pH, and redox status to include the detection of heme. Here, we focus on studies that make use of biosensors to examine mechanisms of heme uptake and degradation, with guidance from the model fungus Saccharomyces cerevisiae and an emphasis on the pathogenic fungi Candida albicans and Cryptococcus neoformans that threaten human health. These studies emphasize a role for endocytosis in heme uptake, and highlight membrane contact sites involving mitochondria, the endoplasmic reticulum and vacuoles as mediators of intracellular iron and heme trafficking.

Keywords: CFEM proteins; Endocytosis; Genetically-encoded sensor; Iron acquisition; Nutritional immunity

DOI: https://doi.org/10.1016/j.fbr.2022.09.002

J Transl Med. 2023 Oct 05. 21(1): 695

TRPA1 promotes cisplatin-induced acute kidney injury via regulating the endoplasmic reticulum stress-mitochondrial damage.

Fei Deng, Heping Zhang, Wei Zhou, Shijie Ma, Yuwei Kang, Wei Yang, Liangbin Zhao, Wei Qin.

BACKGROUND: Cisplatin is a widely used and effective chemotherapeutic agent against cancer. However, nephrotoxicity is one of the most common side effects of cisplatin, and it can proceed to acute kidney injury (AKI). Studies have reported that activation of transient receptor potential ankyrin-1 (TRPA1) mediates cisplatin-induced renal tubular cytotoxic injury. The aim of this study was to investigate the mechanism of TRPA1 in promoting cisplatin-induced AKI through modulation of the endoplasmic reticulum stress (ERS)-mitochondrial damage.METHODS: A cisplatin-induced HK-2 cell model in vitro and mouse model in vivo were established. The mechanism of TRPA1 promotes AKI was elucidated by H&E staining, TUNEL staining, transmission electron microscope (TEM), immunofluorescence, CCK-8 viability assays, flow cytometry, Western blotting, JC-1 assay, and enzyme linked immunosorbent assay (ELISA).
RESULT: In vivo and in vitro, HC-030031 reduced cisplatin-induced Scr and BUN level elevations; improved cisplatin-induced renal tissue injury, apoptosis, and mitochondrial dysfunction; elevated the reduced ERS-associated proteins glucose-regulated protein 78 (GRP78), glucose-regulated protein 75 (GRP75), and C/EBP homologous protein (CHOP) levels induced by cisplatin; reduced the elevated optic atrophy 1 (OPA1), mito-fusion 1 (MFN1), and mito-fusion 2 (MFN2) protein levels, and elevated phospho-dynamin-related protein 1 (p-DRP1) and mitochondrial fission factor (MFF) protein levels. HC-030031 also reduced the mitochondria-associated endoplasmic reticulum membrane (MAM) structure. In addition, TRPA1 agonists also decreased cell proliferation, increased apoptosis, and triggered mitochondrial dysfunction and calcium overload in HK-2 cells via modulation of MAM. ERS inhibitors and GRP75 inhibitors reversed these changes caused by TRPA1 agonists.
CONCLUSION: Our findings suggest that TRPA1 enhances cisplatin-induced AKI via modulation of ERS and mitochondrial damage.

Keywords: Acute kidney injury; Cisplatin; Endoplasmic reticulum stress; Mitochondrial impairment; TRPA1

DOI: https://doi.org/10.1186/s12967-023-04351-9