Wang HX, Wang HM, Lin HY, Yang Q, Zhang H, Tsang BK, Zhu C. J. Cell. Physiol. 2006; 206: 616–623 DOI: 10.1002/jcp.20508
We apologize for the errors. The new Figure 4 is shown below. These corrections do not affect the overall conclusions of the paper.
Damage-associated molecular patterns (DAMPs) are molecules released from damaged or dying cells that contribute to inflammation and cell death. Extracellular ATP, a type of DAMP, has been studied primarily in the context of pyroptosis in monocytes. This study aimed to investigate the role of ATP as a DAMP in mediating pyroptosis within the intestinal mucosal system. Colitis was induced in mice by administering dextran sodium sulfate, followed by analysis of ATP levels and with the expression of pyroptosis-related proteins. Colonic epithelial cells were treated with ATP to assess cell death and pyroptosis levels. Mice with colitis exhibited elevated ATP levels in the colon and serum. Additionally, the expression of pyroptosis-related mediators was significantly upregulated in the colons of these mice. In vitro, ATP treatment increased cell death and mitochondrial dysfunction in colonic epithelial cells. ATP also enhanced inflammatory and pyroptosis responses in these cells, while the expression of apoptosis mediator proteins remained unchanged. Notably, ATP did not further enhance flagellin-induced inflammation. These findings demonstrate that ATP levels are elevated in colitis and that ATP functions as a DAMP to induce pyroptosis in intestinal epithelial cells. This study also highlights a self-propagating cycle where ATP released during pyroptosis triggers further pyroptosis in adjacent cells, exacerbating the condition. Importantly, this study extends our understanding of ATP-mediated pyroptosis to the context of the intestinal mucosal system.
Succinate dehydrogenase (SDH) is both Complex II in the electron transport chain (ETC) and a key metabolic enzyme in the tricarboxylic acid cycle. SDH is a heterotetrameric enzyme consisting of four subunits SDHA, SDHB, SDHC, and SDHD, all encoded in the nuclear genome. In addition, the SDH complex requires two assembly factors, SDHAF1 and SDHAF2, which are required for assembly of SDHA and SDHB onto the inner mitochondrial-embedded subunits SDHC and SDHD. Once assembled, SDH catalyzes the conversion of succinate to fumarate coupled to the reduction of ubiquinone to ubiquinol via FAD/FADH2 and ultimately the generation of ATP via ATP synthase through a functioning ETC. Given the unique dual metabolic role of SDH, loss of activity results in major metabolic rewiring, potentially uncovering metabolic vulnerabilities that could be targeted for pharmacological manipulation in disease states. SDH is a tumor suppressor and SDH-loss is a driver of oncogenesis for cancers including pheochromocytomas, paragangliomas, gastrointestinal stromal tumors, and clear cell renal cell carcinomas. SDH deficiency also plays a role in the pathogenesis in non-neoplastic diseases, including Leigh syndrome and other neurometabolic disorders. Considering the implications of SDH function in both normal physiology and disease, understanding SDH function has fundamental and translational implications. This review seeks to summarize SDH deficiency, focusing on the role SDH plays in metabolism, the metabolic consequences of SDH deficiency, the proteomic consequences of SDH loss, thereby highlight potential therapeutic vulnerabilities in SDH-deficient cells.
Obesity arises from a prolonged state of energy intake exceeding energy expenditure, leading to the “whitening” of brown adipose tissue (BAT) and a decline in metabolic function. To investigate factors contributing to BAT whitening in mice, we used microarray analysis to identify genes differentially expressed in brown adipose-derived stem cells (BADSCs) of wild-type (WT) and ob/ob mice. By intersecting differentially expressed genes between BADSCs and white adipose-derived stem cells (WADSCs) in WT mice, we identified Myl2 as a key gene in BAT function. Myl2 expression showed a 120.8-fold change between ob/ob and WT BADSCs, which was validated by in vivo BAT and in vitro BADSC experiments. Downregulation of Myl2 expression by inhibitor administration significantly reduced the differentiation capacity of BADSCs. Furthermore, overexpression of Myl2 in vitro through adeno-associated virus (AAV) transduction promoted the differentiation of obese mouse-derived BADSCs into brown adipocytes. We further demonstrated the therapeutic potential of Myl2 by administering local injections of Myl2-expressing adeno-associated virus specifically for adipose tissue in ob/ob mice, resulting in improved brown adipose activity and energy metabolism. In summary, this study highlighted the crucial role of Myl2 in BADSC differentiation and BAT function, providing a potential therapeutic target for obesity treatment.
Thomas, J. M., Wang, X., Guo, G., et al. 2020. “GTP-Binding Inhibitors Increase LRRK2-Linked Ubiquitination and Lewy Body-Like Inclusions.” Journal of Cellular Physiology 235: 7309–7320.
The authors, by reviewing the records of the original western blots from this study, recently found that the anti-Flag (tagged LRRK2) blot in Figure 3A (the middle blot of right panel) had been duplicated in Figure 2A (the middle blot of right panel). It has been discovered that the wrong image was inadvertently selected for Figure 2A due to the similarity in the cropped blots. The authors have located the correct blot image for Figure 2A and provided the corrected Figure 2. The conclusions of this paper are not affected by this error.
The authors apologize for this error and any confusion.
EXPRESSION OF CONCERN: G. Gu, I. Barone, L. Gelsomino, C. Giordano, D. Bonofiglio, G. Statti, F. Menichini, S. Catalano, and S. Andò, “Oldenlandia diffusa Extracts Exert Antiproliferative and Apoptotic Effects on Human Breast Cancer Cells Through ERα/Sp1-Mediated p53 Activation,” Journal of Cellular Physiology 227, no. 10 (2012): 3363–3372, https://doi.org/10.1002/jcp.24035.
This Expression of Concern is for the above article, published online on 21 June 2012 in Wiley Online Library (wileyonlinelibrary.com), and has been published by agreement between the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The Expression of Concern has been published due to concerns raised by a third party regarding highly similar image sections between the subpanels of Figures 2B and 5A. The authors’ explanation was found to be insufficient to resolve these concerns, and due to the time elapsed since the original publication, the raw data could no longer be retrieved. In the absence of the original raw data, the journal team could not verify the authenticity of these figures and could not exclude that these concerns affect the related conclusions of the article. Therefore, the journal has decided to issue an Expression of Concern to inform and alert the readers.
Front Cover Caption: The cover image is based on the article Methods to assess neuronal primary cilia electrochemical signaling by Paul G. DeCaen et al., https://doi.org/10.1002/jcp.70075.
Caveolin-1 (Cav1), a protein present in lipid raft invaginations known as caveolae, regulates the trafficking and signaling of some cell surface receptors. Current evidence suggests that the number of caveolae might increase with aging. The parathyroid hormone (PTH) receptor type 1 (PTH1R) regulates osteoblast and osteocyte actions after activation by PTH and PTH-related protein (PTHrP) peptides. PTH1R activation leads to defined biological effects depending on its association with different membrane or intracellular molecules. Since PTH1R exhibits a potential Cav1 binding domain, we hypothesized that PTH1R responses are regulated by Cav1 in cells of the osteoblastic lineage, conditioning PTHrP actions during aging. We report that Cav1 colocalizes with PTH1R at membrane microdomains in osteoblastic and osteocytic cells. Cav1 overexpression modifies PTHrP-dependent signaling in osteoblastic cells by decreasing intracellular calcium accumulation and increasing cAMP levels leading to upregulation of Runx2, osteocalcin, bone alkaline phosphatase, and OPG in a rapid and transient manner. Conversely, Cav1 silencing causes over-phosphorylation of ERK1/2 kinase and overproduction of calcium, which leads to reduced expression of Runx2, osteocalcin, and alkaline phosphatase. Further, the gene expression of Cav1 increases with age in murine bone in vivo and negatively correlates with that of Runx2, osteocalcin and alkaline phosphatase. Moreover, age-dependent overexpression of Cav-1 and caveolae disruption is associated with alterations in PTHrP-dependent bone gene expression in ex vivo cultured bones. FRAP analysis revealed that Cav1 causes PTH1R temporary retention at Cav1 microdomains upon receptor activation, delaying PTH1R internalization. We conclude that PTH1R signaling and PTHrP actions in bone cells are regulated by Cav1 and that Cav1 overexpression with age conditions PTH1R responses in bone.
We attempt to address two key therapeutic obstacles affecting glioblastoma patients: low ability of anticancer drugs to penetrate the blood-brain barrier (BBB), and temozolomide (TMZ) resistance, by targeting mitochondrial respiration of glioblastoma cells. We designed and tested over 100 new compounds based on the chemical structure of fenofibrate (FF), which in its prodrug form is cytotoxic to cancer cells by causing severe impairment of mitochondrial respiration. The compounds were designed using two key predictive tools: central nervous system–multiparameter optimization (CNS-MPO) and BBB_SCORE. These algorithms assess how effectively compounds can penetrate the BBB. We initially selected PP1 as a lead compound by testing its BBB penetration, metabolic performance, and antitumoral efficacy. PP1 accumulated in brain tumors and triggered glioblastoma cell death. However, PP1-induced inhibition of mitochondrial respiration was followed by an immediate glycolytic response, which attenuated PP1 toxicity in a glucose-dependent manner. To bypass this limitation, we tested two strategies: (1) the use of PP1 in combination with glycolysis inhibitors; and (2) introduction of a new compound, PP211, which inhibited mitochondrial respiration in the absence of a concomitant increase of glycolysis. Although the combination of PP1 with glycolysis inhibitors was very effective in vitro, this drug combination demonstrated elevated toxicity in mice. PP211, instead, attenuated TMZ-resistant tumor growth and prolonged mouse survival with only minimal general animal toxicity. In summary, we developed and tested a novel mitochondria-targeting drug candidate, PP211, which effectively crosses the BBB, overcomes TMZ resistance, and induces tumor cell death independently of glucose levels—while exhibiting minimal systemic toxicity in preclinical models. These findings support further development of PP211 for glioblastoma therapy.
As an anthracycline chemotherapy drug, doxorubicin (Dox) is generally prescribed to treat a variety of malignant tumors. Nevertheless, Dox exhibited toxicity at a high dosage, which might eventually lead to injury of the body. Mitochondrial dynamics, including mitochondrial fission and fusion, regulates mitochondrial homeostasis and cellular function. Mounting evidence has demonstrated that imbalance in mitochondrial dynamics, manifested by increased mitochondrial fission or decreased mitochondrial fusion, is associated with the development of Dox-induced diseases. In this paper, we will elaborate the role of mitochondrial dynamics in Dox-induced diseases, and discuss the regulatory mechanism of mitochondrial dynamics in Dox-induced diseases, including apoptosis, fibrosis, myocardial atrophy and inflammation. Elucidating these issues may provide important value in the diagnosis and potential therapeutic strategies for Dox-induced diseases through regulation of mitochondria dynamics.
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