bims-lypmec 2024-05-19 papers

Autophagy. 2024 May 14. 1-2

A delicate decision between repair and degradation of damaged lysosomes.

The destination of a damaged lysosome is either being repaired if the damage is small or degraded through a lysosome-specific macroautophagy/autophagy pathway named lysophagy when the damage is too extensive to repair. Even though previous studies report lumenal glycan exposure during lysosome damage as a signal to trigger lysophagy, it is possibly beneficial for cells to initiate lysophagy earlier than membrane rupture. In a recently published article, Gahlot et al. determined that SPART/SPG20 senses lipid-packing defects and recruits and activates the ubiquitin ligase ITCH, which labels damaged lysosomes with ubiquitin chains to initiate lysophagy.

Keywords: ESCRT; lipid-packing defect; lysophagy; lysosome damage; ubiquitination

DOI: https://doi.org/10.1080/15548627.2024.2350738

J Cell Sci. 2024 May 01. pii: jcs259775. [Epub ahead of print]137(9):

Mammalian pexophagy at a glance.

Justyna Bajdzienko, Anja Bremm.

Peroxisomes are highly plastic organelles that are involved in several metabolic processes, including fatty acid oxidation, ether lipid synthesis and redox homeostasis. Their abundance and activity are dynamically regulated in response to nutrient availability and cellular stress. Damaged or superfluous peroxisomes are removed mainly by pexophagy, the selective autophagy of peroxisomes induced by ubiquitylation of peroxisomal membrane proteins or ubiquitin-independent processes. Dysregulated pexophagy impairs peroxisome homeostasis and has been linked to the development of various human diseases. Despite many recent insights into mammalian pexophagy, our understanding of this process is still limited compared to our understanding of pexophagy in yeast. In this Cell Science at a Glance article and the accompanying poster, we summarize current knowledge on the control of mammalian pexophagy and highlight which aspects require further attention. We also discuss the role of ubiquitylation in pexophagy and describe the ubiquitin machinery involved in regulating signals for the recruitment of phagophores to peroxisomes.

Keywords: Peroxisome; Pexophagy; Selective autophagy; Ubiquitylation

DOI: https://doi.org/10.1242/jcs.259775

Sci Rep. 2024 05 14. 14(1): 10978

TASL mediates keratinocyte differentiation by regulating intracellular calcium levels and lysosomal function.

Ji Yeong Park, Hyeng-Soo Kim, Hyejin Hyung, Soyeon Jang, Jiwon Ko, Jin Hong Lee, Si-Yong Kim, Song Park, Junkoo Yi, Sijun Park, Su-Geun Lim, Seonggon Kim, Sanggyu Lee, Myoung Ok Kim, Soyoung Jang, Zae Young Ryoo.

Maintaining epidermal homeostasis relies on a tightly organized process of proliferation and differentiation of keratinocytes. While past studies have primarily focused on calcium regulation in keratinocyte differentiation, recent research has shed light on the crucial role of lysosome dysfunction in this process. TLR adaptor interacting with SLC15A4 on the lysosome (TASL) plays a role in regulating pH within the endo-lysosome. However, the specific role of TASL in keratinocyte differentiation and its potential impact on proliferation remains elusive. In our study, we discovered that TASL deficiency hinders the proliferation and migration of keratinocytes by inducing G1/S cell cycle arrest. Also, TASL deficiency disrupts proper differentiation process in TASL knockout human keratinocyte cell line (HaCaT) by affecting lysosomal function. Additionally, our research into calcium-induced differentiation showed that TASL deficiency affects calcium modulation, which is essential for keratinocyte regulation. These findings unveil a novel role of TASL in the proliferation and differentiation of keratinocytes, providing new insights into the intricate regulatory mechanisms of keratinocyte biology.

DOI: https://doi.org/10.1038/s41598-024-61674-3

EMBO J. 2024 May 16.

Receptor-mediated cargo hitchhiking on bulk autophagy.

Eigo Takeda, Takahiro Isoda, Sachiko Hosokawa, Yu Oikawa, Shukun Hotta-Ren, Alexander I May, Yoshinori Ohsumi.

While the molecular mechanism of autophagy is well studied, the cargoes delivered by autophagy remain incompletely characterized. To examine the selectivity of autophagy cargo, we conducted proteomics on isolated yeast autophagic bodies, which are intermediate structures in the autophagy process. We identify a protein, Hab1, that is highly preferentially delivered to vacuoles. The N-terminal 42 amino acid region of Hab1 contains an amphipathic helix and an Atg8-family interacting motif, both of which are necessary and sufficient for the preferential delivery of Hab1 by autophagy. We find that fusion of this region with a cytosolic protein results in preferential delivery of this protein to the vacuole. Furthermore, attachment of this region to an organelle allows for autophagic delivery in a manner independent of canonical autophagy receptor or scaffold proteins. We propose a novel mode of selective autophagy in which a receptor, in this case Hab1, binds directly to forming isolation membranes during bulk autophagy.

Keywords: Saccharomyces cerevisiae ; Atg8; Autophagy; Hab1; Selective Autophagy

DOI: https://doi.org/10.1038/s44318-024-00091-8

Circulation. 2024 May 14. 149(20): 1598-1610

Metabolic Reprogramming: A Byproduct or a Driver of Cardiomyocyte Proliferation?

Xiaokang Chen, Hao Wu, Ya Liu, Lingyan Liu, Steven R Houser, Wei Eric Wang.

Defining mechanisms of cardiomyocyte proliferation should guide the understanding of endogenous cardiac regeneration and could lead to novel treatments for diseases such as myocardial infarction. In the neonatal heart, energy metabolic reprogramming (phenotypic alteration of glucose, fatty acid, and amino acid metabolism) parallels cell cycle arrest of cardiomyocytes. The metabolic reprogramming occurring shortly after birth is associated with alterations in blood oxygen levels, metabolic substrate availability, hemodynamic stress, and hormone release. In the adult heart, myocardial infarction causes metabolic reprogramming but these changes cannot stimulate sufficient cardiomyocyte proliferation to replace those lost by the ischemic injury. Some putative pro-proliferative interventions can induce the metabolic reprogramming. Recent data show that altering the metabolic enzymes PKM2 [pyruvate kinase 2], LDHA [lactate dehydrogenase A], PDK4 [pyruvate dehydrogenase kinase 4], SDH [succinate dehydrogenase], CPT1b [carnitine palmitoyl transferase 1b], or HMGCS2 [3-hydroxy-3-methylglutaryl-CoA synthase 2] is sufficient to partially reverse metabolic reprogramming and promotes adult cardiomyocyte proliferation. How metabolic reprogramming regulates cardiomyocyte proliferation is not clearly defined. The possible mechanisms involve biosynthetic pathways from the glycolysis shunts and the epigenetic regulation induced by metabolic intermediates. Metabolic manipulation could represent a new approach to stimulate cardiac regeneration; however, the efficacy of these manipulations requires optimization, and novel molecular targets need to be defined. In this review, we summarize the features, triggers, and molecular regulatory networks responsible for metabolic reprogramming and discuss the current understanding of metabolic reprogramming as a critical determinant of cardiomyocyte proliferation.

Keywords: amino acids; cell cycle; epigenesis, genetic; fatty acids; glucose; metabolic reprogramming; myocytes, cardiac

DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.065880

Int J Mol Sci. 2024 May 05. pii: 5027. [Epub ahead of print]25(9):

Pathophysiology and Advances in the Therapy of Cardiomyopathy in Patients with Diabetes Mellitus.

Patryk Graczyk, Aleksandra Dach, Kamil Dyrka, Andrzej Pawlik.

Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle-a well-balanced diet and physical activity. There is also a group of compounds-including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others-that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM.

Keywords: DCM; DM; GLP-1 analogues; SGLT2 inhibitors; diabetes mellitus; diabetic cardiomyopathy; healthy lifestyle; heart failure; inflammation; metformin; reactive oxygen species; thiazolidinediones

DOI: https://doi.org/10.3390/ijms25095027