bims-lypmec 2023-06-04 papers

Issue of 2023‒06‒04
five papers selected by
Satoru Kobayashi
New York Institute of Technology

Nat Commun. 2023 May 29. 14(1): 3086

Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health.

James L Daly, Chris M Danson, Philip A Lewis, Lu Zhao, Sara Riccardo, Lucio Di Filippo, Davide Cacchiarelli, Daehoon Lee, Stephen J Cross, Kate J Heesom, Wen-Cheng Xiong, Andrea Ballabio, James R Edgar, Peter J Cullen.

Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson's and Alzheimer's diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform an integrated multi-omics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify widespread changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide a holistic view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.

DOI: https://doi.org/10.1038/s41467-023-38719-8

J Diabetes Metab Disord. 2023 Jun;22(1): 47-59

Natural activators of AMPK signaling: potential role in the management of type-2 diabetes.

Sanyogita Chauhan, Aakash Partap Singh, Avtar Chand Rana, Sunil Kumar, Ravi Kumar, Jitender Singh, Ashok Jangra, Dinesh Kumar.

Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase involved in the homeostasis of cellular energy. AMPK has developed as an appealing clinical target for the diagnosis of multiple metabolic diseases such as diabetes mellitus, obesity, inflammation, and cancer. Genetic and pharmacological studies indicate that AMPK is needed in response to glucose deficiency, dietary restriction, and increased physical activity for preserving glucose homeostasis. After activation, AMPK influences metabolic mechanisms contributing to enhanced ATP production, thus growing processes that absorb ATP simultaneously. In this review, several natural products have been discussed which enhance the sensitivity of AMPK and alleviate sub complications or different pathways by which such AMPK triggers can be addressed. AMPK Natural products as potential AMPK activators can be developed as alternate pharmacological intervention to reverse metabolic disorders including type 2 diabetes.

Keywords: AMPK activators; Insulin; Natural products; Type 2 diabetes

DOI: https://doi.org/10.1007/s40200-022-01155-4

Sci Rep. 2023 05 30. 13(1): 8741

Cardiovascular characterisation of a novel mouse model that combines hypertension and diabetes co-morbidities.

Arpeeta Sharma, Judy S Y Choi, Anna M D Watson, Leila Li, Thomas Sonntag, Man K S Lee, Andrew J Murphy, Miles De Blasio, Geoffrey A Head, Rebecca H Ritchie, Judy B de Haan.

Epidemiologic data suggest that the prevalence of hypertension in patients with diabetes mellitus is ∼1.5-2.0 times greater than in matched non-diabetic patients. This co-existent disease burden exacerbates cardiac and vascular injury, leading to structural and functional changes to the myocardium, impaired cardiac function and heart failure. Oxidative stress and persistent low-grade inflammation underlie both conditions, and are identified as major contributors to pathological cardiac remodelling. There is an urgent need for effective therapies that specifically target oxidative stress and inflammation to protect against cardiac remodelling. Animal models are a valuable tool for testing emerging therapeutics, however, there is a notable lack of appropriate animal models of co-morbid diabetes and hypertension. In this study, we describe a novel preclinical mouse model combining diabetes and hypertension to investigate cardiac and vascular pathology of co-morbid disease. Type 1 diabetes was induced in spontaneously hypertensive, 8-week old, male Schlager (BPH/2) mice via 5 consecutive, daily injections of streptozotocin (55 mg/kg in citrate buffer; i.p.). Non-diabetic mice received citrate buffer only. After 10 weeks of diabetes induction, cardiac function was assessed by echocardiography prior to post-mortem evaluation of cardiomyocyte hypertrophy, interstitial fibrosis and inflammation by histology, RT-PCR and flow cytometry. We focussed on the oxidative and inflammatory stress pathways that contribute to cardiovascular remodelling. In particular, we demonstrate that markers of inflammation (monocyte chemoattractant protein; MCP-1), oxidative stress (urinary 8-isoprostanes) and fibrosis (connective tissue growth factor; CTGF) are significantly increased, whilst diastolic dysfunction, as indicated by prolonged isovolumic relaxation time (IVRT), is elevated in this diabetic and hypertensive mouse model. In summary, this pre-clinical mouse model provides researchers with a tool to test therapeutic strategies unique to co-morbid diabetes and hypertension, thereby facilitating the emergence of novel therapeutics to combat the cardiovascular consequences of these debilitating co-morbidities.

DOI: https://doi.org/10.1038/s41598-023-35680-w

Front Mol Biosci. 2023 ;10 1203269

Emerging field: O-GlcNAcylation in ferroptosis.

Hongshuo Zhang, Juan Zhang, Haojie Dong, Ying Kong, Youfei Guan.

In 2012, researchers proposed a non-apoptotic, iron-dependent form of cell death caused by lipid peroxidation called ferroptosis. During the past decade, a comprehensive understanding of ferroptosis has emerged. Ferroptosis is closely associated with the tumor microenvironment, cancer, immunity, aging, and tissue damage. Its mechanism is precisely regulated at the epigenetic, transcriptional, and post-translational levels. O-GlcNAc modification (O-GlcNAcylation) is one of the post-translational modifications of proteins. Cells can modulate cell survival in response to stress stimuli, including apoptosis, necrosis, and autophagy, through adaptive regulation by O-GlcNAcylation. However, the function and mechanism of these modifications in regulating ferroptosis are only beginning to be understood. Here, we review the relevant literature within the last 5 years and present the current understanding of the regulatory function of O-GlcNAcylation in ferroptosis and the potential mechanisms that may be involved, including antioxidant defense system-controlled reactive oxygen species biology, iron metabolism, and membrane lipid peroxidation metabolism. In addition to these three areas of ferroptosis research, we examine how changes in the morphology and function of subcellular organelles (e.g., mitochondria and endoplasmic reticulum) involved in O-GlcNAcylation may trigger and amplify ferroptosis. We have dissected the role of O-GlcNAcylation in regulating ferroptosis and hope that our introduction will provide a general framework for those interested in this field.

Keywords: O-GlcNAcylation; ROS biology; ferroptosis; iron metabolism; lipid peroxidation; subcellular organelle

DOI: https://doi.org/10.3389/fmolb.2023.1203269

FEBS Lett. 2023 Jun 01.

ER-to-Lysosome Associated Degradation (ERLAD) in a Nutshell: mammalian, yeast and plant ER-phagy as induced by misfolded proteins.

Mikhail Rudinskiy, Maurizio Molinari.

Conserved catabolic pathways operate to remove aberrant polypeptides from the endoplasmic reticulum (ER), the major biosynthetic organelle of eukaryotic cells. The best known are the ER-associated degradation (ERAD) pathways that control retro-translocation of terminally misfolded proteins across the ER membrane for clearance by the cytoplasmic ubiquitin/proteasome system. In this review, we catalogue folding-defective mammalian, yeast, and plant proteins that fail to engage ERAD machineries. We describe that they rather segregate in ER subdomains that eventually vesiculate. These ER-derived vesicles are captured by double membrane autophagosomes, engulfed by endolysosomes/vacuoles, or fuse with degradative organelles to clear cells from their toxic cargo. These client-specific, mechanistically diverse ER-phagy pathways are grouped under the umbrella term of ER-to-Lysosome-Associated Degradation (ERLAD) for description in this essay.

Keywords: ER-Associated Degradation (ERAD); ER-phagy; ER-to-Lysosome-Associated degradation (ERLAD); Lysosome/vacuole; Ubiquitin/proteasome system

DOI: https://doi.org/10.1002/1873-3468.14674