bims-mecosi 2023-03-12 papers

Issue of 2023‒03‒12
four papers selected by
Verena Kohler

Handb Exp Pharmacol. 2023 Mar 08.

Lysosomal Ion Channels and Lysosome-Organelle Interactions.

Weijie Cai, Ping Li, Mingxue Gu, Haoxing Xu.

Intracellular organelles exchange their luminal contents with each other via both vesicular and non-vesicular mechanisms. By forming membrane contact sites (MCSs) with ER and mitochondria, lysosomes mediate bidirectional transport of metabolites and ions between lysosomes and organelles that regulate lysosomal physiology, movement, membrane remodeling, and membrane repair. In this chapter, we will first summarize the current knowledge of lysosomal ion channels and then discuss the molecular and physiological mechanisms that regulate lysosome-organelle MCS formation and dynamics. We will also discuss the roles of lysosome-ER and lysosome-mitochondria MCSs in signal transduction, lipid transport, Ca 2+ transfer, membrane trafficking, and membrane repair, as well as their roles in lysosome-related pathologies.

Keywords: ER; Lysosomes; Membrane contact sites; Mitochondria; TRPML1

DOI: https://doi.org/10.1007/164_2023_640

Biochem Soc Trans. 2023 Mar 09. pii: BST20221305. [Epub ahead of print]

New discoveries in ER-mitochondria communication.

Margret Helene Bülow, Julia Sellin.

The study of endoplasmic reticulum (ER)-mitochondria communication is a vast and expanding field with many novel developments in the past few years. In this mini-review, we focus on several recent publications that identify novel functions of tether complexes, in particular autophagy regulation and lipid droplet biogenesis. We review novel findings that shed light on the role of triple contacts between ER and mitochondria with peroxisomes or lipid droplets as the third player. We also summarize recent findings on the role of ER-mitochondria contacts in human neurodegenerative diseases, which implicate either enhanced or reduced ER-mitochondria contacts in neurodegeneration. Taken together, the discussed studies highlight the need for further research into the role of triple organelle contacts, as well as into the exact mechanisms of increased and decreased ER-mitochondria contacts in neurodegeneration.

Keywords: endoplasmic reticulum; mitochondria; neurodegeneration; organelles

DOI: https://doi.org/10.1042/BST20221305

J Biol Chem. 2023 Mar 03. pii: S0021-9258(23)00223-5. [Epub ahead of print] 104581

A protein bridge to death between the ER and mitochondria.

Jialing Lin.

Commitment to apoptotic cell death occurs at the mitochondria, and is regulated by BCL-2 family proteins localized to this organelle. However, BIK, a resident protein of the endoplasmic reticulum inhibits mitochondrial BCL-2 proteins to promote apoptosis. In a recent paper in the JBC, Osterlund et al. investigated this conundrum. Surprisingly, they discovered that these endoplasmic reticulum and mitochondrial proteins moved toward each other and met at the contact site between the two organelles, thereby forming a 'bridge to death'.

DOI: https://doi.org/10.1016/j.jbc.2023.104581

J Clin Med. 2023 Feb 24. pii: 1830. [Epub ahead of print]12(5):

Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Is a Promising Signature to Predict Prognosis and Therapies for Hepatocellular Carcinoma (HCC).

Yuyan Chen, Senzhe Xia, Lu Zhang, Xueqian Qin, Zhengyi Zhu, Tao Ma, Shushu Lu, Jing Chen, Xiaolei Shi, Haozhen Ren.

BACKGROUND: The roles of mitochondria and the endoplasmic reticulum (ER) in the progression of hepatocellular carcinoma (HCC) are well established. However, a special domain that regulates the close contact between the ER and mitochondria, known as the mitochondria-associated endoplasmic reticulum membrane (MAM), has not yet been investigated in detail in HCC.METHODS: The TCGA-LIHC dataset was only used as a training set. In addition, the ICGC and several GEO datasets were used for validation. Consensus clustering was applied to test the prognostic value of the MAM-associated genes. Then, the MAM score was constructed using the lasso algorithm. In addition, uncertainty of clustering in single-cell RNA-seq data using a gene co-expression network (AUCell) was used for the detection of the MAM scores in various cell types. Then, CellChat analysis was applied for comparing the interaction strength between the different MAM score groups. Further, the tumor microenvironment score (TME score) was calculated to compare the prognostic values, the correlation with the other HCC subtypes, tumor immune infiltration landscape, genomic mutations, and copy number variations (CNV) of different subgroups. Finally, the response to immune therapy and sensitivity to chemotherapy were also determined.
RESULTS: First, it was observed that the MAM-associated genes could differentiate the survival rates of HCC. Then, the MAM score was constructed and validated using the TCGA and ICGC datasets, respectively. The AUCell analysis indicated that the MAM score was higher in the malignant cells. In addition, enrichment analysis demonstrated that malignant cells with a high MAM score were positively correlated with energy metabolism pathways. Furthermore, the CellChat analysis indicated that the interaction strength was reinforced between the high-MAM-score malignant cells and T cells. Finally, the TME score was constructed, which demonstrated that the HCC patients with high MAM scores/low TME scores tend to have a worse prognosis and high frequency of genomic mutations, while those with low MAM scores/high TME scores were more likely to have a better response to immune therapy.
CONCLUSIONS: MAM score is a promising index for determining the need for chemotherapy, which reflects the energy metabolic pathways. A combination of the MAM score and TME score could be a better indicator to predict prognosis and response to immune therapy.

Keywords: chemotherapy; hepatocellular carcinoma; immune therapy; mitochondria-associated endoplasmic reticulum membrane; tumor microenvironment

DOI: https://doi.org/10.3390/jcm12051830