β-cell mitochondria in diabetes mellitus: a missing puzzle piece in the generation of hPSC-derived pancreatic β-cells?

Diané, Abdoulaye; Al-Shukri, Noora Ali; Mu-u-min, Razik; Al-Siddiqi, Heba

doi:10.1186/s12967-022-03327-5

Cited by 10 publications

(5 citation statements)

References 110 publications

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“…The maintenance of a healthy mitochondrial network, fundamental to support cell energy demand, is strictly dependent on mitochondrial fission and fusion dynamics, a process regulating changes in mitochondrial size and shape, growth and redistribution, as well as intervening in mitochondrial cristae remodeling [ 53 ]. Such a “mitochondrial quality control” system has been found frequently deregulated in pathological conditions, including cardiovascular diseases [ 8 , 54 ], non-alcoholic fatty liver disease [ 55 ], acute kidney injury [ 56 ], neurodegenerative disorders [ 57 , 58 ], diabetes mellitus [ 59 ], skeletal muscle atrophy [ 60 ], and many others.…”

Section: Discussionmentioning

confidence: 99%

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

Torcasio,

Gallo Cantafio,

Veneziano

et al. 2024

J Transl Med

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Background Mitochondrial alterations, often dependent on unbalanced mitochondrial dynamics, feature in the pathobiology of human cancers, including multiple myeloma (MM). Flavanones are natural flavonoids endowed with mitochondrial targeting activities. Herein, we investigated the capability of Hesperetin (Hes) and Naringenin (Nar), two aglycones of Hesperidin and Naringin flavanone glycosides, to selectively target Drp1, a pivotal regulator of mitochondrial dynamics, prompting anti-MM activity. Methods Molecular docking analyses were performed on the crystallographic structure of Dynamin-1-like protein (Drp1), using Hes and Nar molecular structures. Cell viability and apoptosis were assessed in MM cell lines, or in co-culture systems with primary bone marrow stromal cells, using Cell Titer Glo and Annexin V-7AAD staining, respectively; clonogenicity was determined using methylcellulose colony assays. Transcriptomic analyses were carried out using the Ion AmpliSeq™ platform; mRNA and protein expression levels were determined by quantitative RT-PCR and western blotting, respectively. Mitochondrial architecture was assessed by transmission electron microscopy. Real time measurement of oxygen consumption was performed by high resolution respirometry in living cells. In vivo anti-tumor activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells. Results Hes and Nar were found to accommodate within the GTPase binding site of Drp1, and to inhibit Drp1 expression and activity, leading to hyperfused mitochondria with reduced OXPHOS. In vitro, Hes and Nar reduced MM clonogenicity and viability, even in the presence of patient-derived bone marrow stromal cells, triggering ER stress and apoptosis. Interestingly, Hes and Nar rewired MM cell metabolism through the down-regulation of master transcriptional activators (SREBF-1, c-MYC) of lipogenesis genes. An extract of Tacle, a Citrus variety rich in Hesperidin and Naringin, was capable to recapitulate the phenotypic and molecular perturbations of each flavanone, triggering anti-MM activity in vivo. Conclusion Hes and Nar inhibit proliferation, rewire the metabolism and induce apoptosis of MM cells via antagonism of the mitochondrial fission driver Drp1. These results provide a framework for the development of natural anti-MM therapeutics targeting aberrant mitochondrial dependencies.

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Section: Discussionmentioning

confidence: 99%

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

Torcasio,

Gallo Cantafio,

Veneziano

et al. 2024

J Transl Med

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“…Multiple mechanisms are involved in the impaired GSIS. ER and mitochondria are two pivotal organelles involved in the function and survival of β-cells ( 11 , 67 ). In vivo and in vitro studies have highlighted distinct or combined role of ER stress and mitochondria dysfunction in β-cell functionality ( 11 , 68 ).…”

Section: Role Of Er Stress In the Functionality Of Hpsc-derived Pancr...mentioning

confidence: 99%

Endoplasmic reticulum stress in pancreatic β-cell dysfunctionality and diabetes mellitus: a promising target for generation of functional hPSC-derived β-cells in vitro

Diane,

Allouch,

Mu-U-Min

et al. 2024

Front. Endocrinol.

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Diabetes mellitus (DM), is a chronic disorder characterized by impaired glucose homeostasis that results from the loss or dysfunction of pancreatic β-cells leading to type 1 diabetes (T1DM) and type 2 diabetes (T2DM), respectively. Pancreatic β-cells rely to a great degree on their endoplasmic reticulum (ER) to overcome the increased secretary need for insulin biosynthesis and secretion in response to nutrient demand to maintain glucose homeostasis in the body. As a result, β-cells are potentially under ER stress following nutrient levels rise in the circulation for a proper pro-insulin folding mediated by the unfolded protein response (UPR), underscoring the importance of this process to maintain ER homeostasis for normal β-cell function. However, excessive or prolonged increased influx of nascent proinsulin into the ER lumen can exceed the ER capacity leading to pancreatic β-cells ER stress and subsequently to β-cell dysfunction. In mammalian cells, such as β-cells, the ER stress response is primarily regulated by three canonical ER-resident transmembrane proteins: ATF6, IRE1, and PERK/PEK. Each of these proteins generates a transcription factor (ATF4, XBP1s, and ATF6, respectively), which in turn activates the transcription of ER stress-inducible genes. An increasing number of evidence suggests that unresolved or dysregulated ER stress signaling pathways play a pivotal role in β-cell failure leading to insulin secretion defect and diabetes. In this article we first highlight and summarize recent insights on the role of ER stress and its associated signaling mechanisms on β-cell function and diabetes and second how the ER stress pathways could be targeted in vitro during direct differentiation protocols for generation of hPSC-derived pancreatic β-cells to faithfully phenocopy all features of bona fide human β-cells for diabetes therapy or drug screening.

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“…Although it can be sourced from different cellular compartments, the mitochondrial electron transport chain remains the major source of ROS within preclinal models and human systems[ 111 ]. The pancreatic β-cells contain mitochondria, which is vital for the regulation of glucose-stimulated insulin release by coupling glucose metabolism to insulin exocytosis[ 112 ]. Sustained exposure to hyperglycemic conditions has been associated with impaired β-cell dysfunction through diverse biochemical and molecular mechanisms that implicate impaired oxidation phosphorylation, enhanced production of advanced glycation end products, and abnormal activation of protein kinase C, as well as the polyol and hexosamine pathways[ 14 ].…”

Section: Oxidative Stress and Pancreatic β-Cell Dysfunction In T2dmentioning

confidence: 99%

Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress

Dludla¹,

Mabhida²,

Ziqubu³

et al. 2023

World J Diabetes

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Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D. Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. Such effects illustrate a pathological relationship between an abnormal inflammatory response and generation of oxidative stress during the progression of T2D. The current review explores preclinical and clinical research on the patho-logical implications of inflammation and oxidative stress during the development of β-cell dysfunction in T2D. Moreover, important molecular mechanisms and relevant biomarkers involved in this process are discussed to divulge a pathological link between inflammation and oxidative stress during β-cell failure in T2D. Underpinning the clinical relevance of the review, a systematic analysis of evidence from randomized controlled trials is covered, on the potential therapeutic effects of some commonly used antidiabetic agents in modulating inflammatory makers to improve β-cell function.

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β-cell mitochondria in diabetes mellitus: a missing puzzle piece in the generation of hPSC-derived pancreatic β-cells?

Cited by 10 publications

References 110 publications

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

Endoplasmic reticulum stress in pancreatic β-cell dysfunctionality and diabetes mellitus: a promising target for generation of functional hPSC-derived β-cells in vitro

Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress

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