bims-lycede 2024-10-06 papers

J Cell Biol. 2024 Dec 02. pii: e202403195. [Epub ahead of print]223(12):

Migratory autolysosome disposal mitigates lysosome damage.

Takami Sho, Ying Li, Haifeng Jiao, Li Yu.

Lysosomes, essential for intracellular degradation and recycling, employ damage-control strategies such as lysophagy and membrane repair mechanisms to maintain functionality and cellular homeostasis. Our study unveils migratory autolysosome disposal (MAD), a response to lysosomal damage where cells expel LAMP1-LC3 positive structures via autolysosome exocytosis, requiring autophagy machinery, SNARE proteins, and cell migration. This mechanism, crucial for mitigating lysosomal damage, underscores the role of cell migration in lysosome damage control and facilitates the release of small extracellular vesicles, highlighting the intricate relationship between cell migration, organelle quality control, and extracellular vesicle release.

DOI: https://doi.org/10.1083/jcb.202403195

Int J Mol Sci. 2024 Sep 19. pii: 10070. [Epub ahead of print]25(18):

Lysosomal Proteases and Their Inhibitors.

Vito Turk, Veronika Stoka.

The discovery of the lysosome, a major cytoplasmic organelle, represents a breakthrough in the understanding of intracellular protein degradation processes-proteolysis [...].

DOI: https://doi.org/10.3390/ijms251810070

Biochim Biophys Acta Mol Cell Res. 2024 Sep 29. pii: S0167-4889(24)00196-4. [Epub ahead of print] 119853

An artificial peptide inhibits autophagy through calcineurin-TFEB pathway.

Yumeng Yang, Yanan Li, Hanxiao Shang, Yueyang Liu, Wenying Li, Limin Chen, Na Cheng, Yuchen Zhang, Nan Zhang, Yanxia Yin, Li Tong, Zhimei Li, Jingyu Yang, Jing Luo.

We previously reported that a bioactive peptide (pep3) can potently inhibit the enzyme activity of purified calcineurin (CN). In this paper, we further demonstrate that transfected pep3 can strongly inhibit CN enzyme activity in HEK293 cells. Transcription factor EB (TFEB) plays an important role in the autophagy-lysosome pathway (ALP) as one of the substrates of CN, so we study the effect of pep3 on the CN-TFEB-ALP pathway. Pep3 can significantly inhibit the mRNA levels of the TFEB downstream genes and the expression of the autophagy-associated proteins, and autophagy flux in HEK293 cells. We also validated the inhibitory effect of pep3 on autophagy in mice. These findings may provide a new idea for discovering more CN inhibitors and autophagy inhibitory drugs.

Keywords: Autophagy-lysosome pathway; Calcineurin; Inhibitor; Pep3; Transcription factor EB

DOI: https://doi.org/10.1016/j.bbamcr.2024.119853

Pharmaceutics. 2024 Sep 04. pii: 1167. [Epub ahead of print]16(9):

Subcellular Drug Distribution: Exploring Organelle-Specific Characteristics for Enhanced Therapeutic Efficacy.

Xin Liu, Miaomiao Li, Sukyung Woo.

The efficacy and potential toxicity of drug treatments depends on the drug concentration at its site of action, intricately linked to its distribution within diverse organelles of mammalian cells. These organelles, including the nucleus, endosome, lysosome, mitochondria, endoplasmic reticulum, Golgi apparatus, lipid droplets, exosomes, and membrane-less structures, create distinct sub-compartments within the cell, each with unique biological features. Certain structures within these sub-compartments possess the ability to selectively accumulate or exclude drugs based on their physicochemical attributes, directly impacting drug efficacy. Under pathological conditions, such as cancer, many cells undergo dynamic alterations in subcellular organelles, leading to changes in the active concentration of drugs. A mechanistic and quantitative understanding of how organelle characteristics and abundance alter drug partition coefficients is crucial. This review explores biological factors and physicochemical properties influencing subcellular drug distribution, alongside strategies for modulation to enhance efficacy. Additionally, we discuss physiologically based computational models for subcellular drug distribution, providing a quantifiable means to simulate and predict drug distribution at the subcellular level, with the potential to optimize drug development strategies.

Keywords: computational pharmacokinetic modeling; drug efficacy; drug resistance; organelle targeting; subcellular drug distribution

DOI: https://doi.org/10.3390/pharmaceutics16091167