bims-lypmec 2024-09-01 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2024‒09‒01
six papers selected by
Satoru Kobayashi, New York Institute of Technology

Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
RILP Induces Cholesterol Accumulation in Lysosomes by Inhibiting Endoplasmic Reticulum-Endolysosome Interactions.
Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.
USP8 PROMOTES INTRACELLULAR INFECTION by ENHANCING ESCRT-MEDIATED MEMBRANE REPAIR, LIMITING XENOPHAGY, and REDUCING OXIDATIVE STRESS.
Intermittent fasting increases fat oxidation and promotes metabolic flexibility in lean mice but not obese type 2 diabetic mice.
Current and future perspectives of single-cell multi-omics technologies in cardiovascular research.

Int J Mol Sci. 2024 Aug 15. pii: 8884. [Epub ahead of print]25(16):

Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?

Nadia Papini, Paola Giussani, Cristina Tringali.

  Metformin is a widely employed drug in type 2 diabetes. In addition to warranting good short- and long-term glycemic control, metformin displays many intriguing properties as protection against cardiovascular and neurodegenerative diseases, anti-tumorigenic and longevity promotion. In addition to being a low-cost drug, metformin is generally well tolerated. However, despite the enthusiastic drive to aliment these novel studies, many contradictory results suggest the importance of better elucidating the complexity of metformin action in different tissues/cells to establish its possible employment in neurodegenerative diseases. This review summarises recent data identifying lysosomal-dependent processes and lysosomal targets, such as endosomal Na+/H+ exchangers, presenilin enhancer 2 (PEN2), the lysosomal pathway leading to AMP-activated protein kinase (AMPK) activation, and the transcription factor EB (TFEB), modulated by metformin. Lysosomal dysfunctions resulting in autophagic and lysosomal acidification and biogenesis impairment appear to be hallmarks of many inherited and acquired neurodegenerative diseases. Lysosomes are not yet seen as a sort of cellular dump but are crucial in determining key signalling paths and processes involved in the clearance of aggregated proteins. Thus, the possibility of pharmacologically modulating them deserves great interest. Despite the potentiality of metformin in this context, many additional important issues, such as dosing, should be addressed in the future.

Keywords:  lysosome; metformin; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms25168884
Cells. 2024 Aug 06. pii: 1313. [Epub ahead of print]13(16):

RILP Induces Cholesterol Accumulation in Lysosomes by Inhibiting Endoplasmic Reticulum-Endolysosome Interactions.

Yang Han, Xiaoqing Liu, Liju Xu, Ziheng Wei, Yueting Gu, Yandan Ren, Wenyi Hua, Yongtao Zhang, Xiaoxi Liu, Cong Jiang, Ruijuan Zhuang, Wanjin Hong, Tuanlao Wang.

  Endoplasmic reticulum (ER)-endolysosome interactions regulate cholesterol exchange between the ER and the endolysosome. ER-endolysosome membrane contact sites mediate the ER-endolysosome interaction. VAP-ORP1L (vesicle-associated membrane protein-associated protein- OSBP-related protein 1L) interaction forms the major contact site between the ER and the lysosome, which is regulated by Rab7. RILP (Rab7-interacting lysosomal protein) is the downstream effector of Rab7, but its role in the organelle interaction between the ER and the lysosome is not clear. In this study, we found RILP interacts with ORP1L to competitively inhibit the formation of the VAP-ORP1L contact site. Immunofluorescence microscopy revealed that RILP induces late endosome/lysosome clustering, which reduces the contact of endolysosomes with the ER, interfering with the ER-endolysosome interaction. Further examination demonstrated that over-expression of RILP results in the accumulation of cholesterol in the clustered endolysosomes, which triggers cellular autophagy depending on RILP. Our results suggest that RILP interferes with the ER-endolysosome interaction to inhibit cholesterol flow from the endolysosome to the ER, which feedbacks to trigger autophagy.

Keywords:  RILP; Rab7; autophagy; cholesterol transport; organelle interaction

DOI:  https://doi.org/10.3390/cells13161313
J Cell Biol. 2024 Nov 04. pii: e202308099. [Epub ahead of print]223(11):

Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.

Yewei Huang, Gan Luo, Kesong Peng, Yue Song, Yusha Wang, Hongtao Zhang, Jin Li, Xiangmin Qiu, Maomao Pu, Xinchang Liu, Chao Peng, Dante Neculai, Qiming Sun, Tianhua Zhou, Pintong Huang, Wei Liu.

The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells.

DOI: https://doi.org/10.1083/jcb.202308099
Autophagy. 2024 Aug 23.

USP8 PROMOTES INTRACELLULAR INFECTION by ENHANCING ESCRT-MEDIATED MEMBRANE REPAIR, LIMITING XENOPHAGY, and REDUCING OXIDATIVE STRESS.

Pallavi Chandra, Jennifer A Philips.

  The host ESCRT-machinery repairs damaged endolysosomal membranes. If damage persists, selective macroautophagy/autophagy clears the damaged compartment. Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that damages the phagosomal membrane and targets ESCRT-mediated repair as part of its virulence program. The E3 ubiquitin ligases PRKN and SMURF1 promote autophagic capture of damaged, Mtb-containing phagosomes. Because ubiquitination is a reversible process, we anticipated that host deubiquitinases (DUBs) would also be involved. Here, we screened all predicted mouse DUBs for their role in ubiquitin targeting and control of intracellular Mtb. We show that USP8 (ubiquitin specific peptidase 8) colocalizes with intracellular Mtb, recognizes phagosomal membrane damage, and is required for ESCRT-dependent membrane repair. Furthermore, we show that USP8 regulates the NFE2L2/NRF2-dependent antioxidant signature. Taken together, our study demonstrates a central role of USP8 in promoting Mtb intracellular growth by promoting phagosomal membrane repair, limiting ubiquitin-driven selective autophagy, and reducing oxidative stress.

Keywords:  Autophagy; deubiquitinase; endomembrane damage; mycobacterium tuberculosis

DOI:  https://doi.org/10.1080/15548627.2024.2395134
Am J Physiol Endocrinol Metab. 2024 Aug 28.

Intermittent fasting increases fat oxidation and promotes metabolic flexibility in lean mice but not obese type 2 diabetic mice.

Meghan O Conn, Daniel M Marko, Jonathan D Schertzer.

  Obesity and type 2 diabetes (T2D) are associated with metabolic inflexibility, characterized by an impaired ability to switch between substrate storage and utilization pathways. Metabolic inflexibility during obesity is typified by lower engagement of fatty acid metabolism despite an ample supply of stored lipids. Intermittent fasting (IF) can promote metabolic flexibility. However, it is not clear how obesity and T2D alter metabolic flexibility after repeated IF. Male obese db/db and control db/+ mice were fasted for 24 hours twice a week for 10 weeks. This 5:2 IF regimen did not alter body mass, body composition, food intake, or physical activity in db/db or db/+ mice. After IF, db/db mice had lower fatty acid oxidation and higher carbohydrate oxidation in the fed state, indicating metabolic inflexibility to metabolize lipids. After IF, control db/+ mice had higher fatty acid oxidation and lower carbohydrate oxidation in the fed state, characteristic of metabolic flexibility and increased engagement of lipid metabolism. In the fasted state, IF lowered carbohydrate oxidation and increased fatty acid oxidation in control db/+ mice but not in obese db/db mice. After IF, db/db mice also had lower serum β-hydroxybutyrate than control db/+ mice. 10 weeks of IF decreased adipocyte size in visceral adipose tissue of control db/+ mice, but this IF regimen did not change adipocyte size in obese db/db mice. Therefore, IF increases fatty acid oxidation and metabolic flexibility in lean mice, but this adaptation is absent in a mouse model of obesity and type 2 diabetes.

Keywords:  Insulin; Intermittent Fasting; Obesity; Type 2 Diabetes; mice

DOI:  https://doi.org/10.1152/ajpendo.00255.2024
Nat Cardiovasc Res. 2023 Jan;2(1): 20-34

Current and future perspectives of single-cell multi-omics technologies in cardiovascular research.

Wilson Lek Wen Tan, Wei Qiang Seow, Angela Zhang, Siyeon Rhee, Wing H Wong, William J Greenleaf, Joseph C Wu.

Single-cell technology has become an indispensable tool in cardiovascular research since its first introduction in 2009. Here, we highlight the recent remarkable progress in using single-cell technology to study transcriptomic and epigenetic heterogeneity in cardiac disease and development. We then introduce the key concepts in single-cell multi-omics modalities that apply to cardiovascular research. Lastly, we discuss some of the trending concepts in single-cell technology that are expected to propel cardiovascular research to the next phase of single-cell research.

DOI: https://doi.org/10.1038/s44161-022-00205-7