bims-lypmec 2023-10-22 papers

Traffic. 2023 Oct 17.

Copper-independent lysosomal localisation of the Wilson disease protein ATP7B.

Saptarshi Maji, Marinella Pirozzi, Ruturaj, Raviranjan Pandey, Tamal Ghosh, Santanu Das, Arnab Gupta.

In hepatocytes, the Wilson disease protein ATP7B resides on the trans-Golgi network (TGN) and traffics to peripheral lysosomes to export excess intracellular copper through lysosomal exocytosis. We found that in basal copper or even upon copper chelation, a significant amount of ATP7B persists in the endolysosomal compartment of hepatocytes but not in non-hepatic cells. These ATP7B-harbouring lysosomes lie in close proximity of ~10 nm to the TGN. ATP7B constitutively distributes itself between the sub-domain of the TGN with a lower pH and the TGN-proximal lysosomal compartments. The presence of ATP7B on TGN-lysosome colocalising sites upon Golgi disruption suggested a possible exchange of ATP7B directly between the TGN and its proximal lysosomes. Manipulating lysosomal positioning significantly alters the localisation of ATP7B in the cell. Contrary to previous understanding, we found that upon copper chelation in a copper-replete hepatocyte, ATP7B is not retrieved back to TGN from peripheral lysosomes; rather, ATP7B recycles to these TGN-proximal lysosomes to initiate the next cycle of copper transport. We report a hitherto unknown copper-independent lysosomal localisation of ATP7B and the importance of TGN-proximal lysosomes but not TGN as the terminal acceptor organelle of ATP7B in its retrograde pathway.

Keywords: ATP7B; TGN-endolysosome contact; TGN-proximal lysosomes; Wilson disease; endolysosomes; hepatocytes; trans-Golgi network

DOI: https://doi.org/10.1111/tra.12919

Autophagy Rep. 2022 ;1(1): 197-200

Lipid droplets in stress protection: distinct mechanisms of lipid droplet microautophagy.

Pin-Chao Liao, Liza A Pon.

Lipid droplets (LDs) are organelles that function as sites for lipid storage. LDs have also been implicated in the cellular response to proteotoxic or lipotoxic stress as sites for sequestering dysfunctional or excess proteins or lipids, and targeting those cargos for degradation by LD microautophagy (microlipophagy, μLP). Here, we describe two mechanisms for μLP in yeast, which are triggered by different stressors. μLP occurs at raft-like liquid ordered microdomains in the vacuolar membrane in yeast exposed to severe nutrient limitations. In contrast, in yeast exposed to ER stress or less severe nutrient limitations, LD uptake at the vacuole is liquid ordered (Lo) microdomain-independent and dependent upon vacuolar membrane remodeling mediated by endosomal sorting complexes required for transport (ESCRT).

DOI: https://doi.org/10.1080/27694127.2022.2067643

Mo Med. 2023 Sep-Oct;120(5):120(5): 354-358

Metabolic Drivers and Rescuers of Heart Failure.

Rachel C Weiss, Thiago N Menezes, Kyle S McCommis.

Cardiac hypertrophy and heart failure involve a number of metabolic alterations. Human genetic mutations and murine genetic deficiency models of metabolic enzymes or transporters largely suggest that these alterations in metabolism are maladaptive and contribute to the cardiac remodeling and dysfunction. Here, we discuss insights into metabolic alterations identified in cardiac hypertrophy and failure, as well as dietary and pharmacologic therapies that counteract these metabolic alterations and have been shown to significantly improve heart failure.

Cureus. 2023 Sep;15(9): e45290

How Does It Work? Unraveling the Mysteries by Which Empagliflozin Helps Diabetic and Non-diabetic Patients With Heart Failure.

Vernicia K Hernandez, Brad T Parks Melville, Khadijah Siwaju.

In patients with heart failure, empagliflozin offers significant cardiovascular benefits. However, its exact mode of action is unknown. Understanding the way by which empagliflozin works in heart failure may uncover additional therapeutic targets or identify other classes of drugs that may be useful to clinicians and patients. This literature review aims to unravel the mysteries by which empagliflozin reduces cardiovascular death, cardiovascular events, and heart failure hospitalization in diabetic and non-diabetic patients. Three researchers conducted the data collection. We incorporated research that used human models, animal models, patients with diabetes, and patients without diabetes. Pathology, pathophysiology, metabolism, physiology, empagliflozin, heart failure, and cardiovascular were the search terms used to probe the mesh database on PubMed. This study showed that the mechanisms by which empagliflozin could lead to positive clinical outcomes in heart failure (HF) are as follows: down-regulation of the mammalian target of rapamycin complex 1 signaling (mTORC), decreasing sarcoplasmic reticulum calcium loss, increasing cytosolic calcium loss, inducing electrolyte-free osmotic diuresis, improving fuel efficiency, and protecting the endothelial glycocalyx. These findings were inconsistent, with no generally accepted hypotheses within the scientific community. Hence we conclude that further research is required to determine the function of Empagliflozin in heart failure and the degree to which the aforementioned mechanisms of action contribute to cardiac protection.

Keywords: cardiovascular effect; diabetic patient; empagliflozin; heart failure knowledge; sodium-glucose cotransporter-2 (sglt2) inhibitors

DOI: https://doi.org/10.7759/cureus.45290

Cell Rep. 2023 Oct 19. pii: S2211-1247(23)01303-7. [Epub ahead of print]42(10): 113291

Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.

Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.

Keywords: ATG5; CP: Cell biology; DRP1; autophagy; hepatocytes; lysosome; mitophagy

DOI: https://doi.org/10.1016/j.celrep.2023.113291