SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I

Ciscato, Francesco; Sciacovelli, Marco; Villano, Gianmarco; Turato, Cristian; Bernardi, Paolo; Rasola, Andrea; Pontisso, Patrizia

doi:10.18632/oncotarget.1411

Cited by 60 publications

(78 citation statements)

References 47 publications

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“…6D). On the other hand, when another cell-death stimulus such as etoposide, which acts independently of mitochondrial Ca 2+ overload toxicity (33,34), was applied to control and Mfn2-KD cells, no difference was found in the number of annexin-V + cells (Fig. 6C), strongly suggesting a causal relationship between Mfn2, ER-mitochondria Ca 2+ transfer, and celldeath sensitivity.…”

Section: Mfn2 Ablation Does Not Alter the Dynamics Of Er-mitochondriamentioning

confidence: 95%

Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling

Filadi

Greotti

Turacchio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

486

432

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The organization and mutual interactions between endoplasmic reticulum (ER) and mitochondria modulate key aspects of cell pathophysiology. Several proteins have been suggested to be involved in keeping ER and mitochondria at a correct distance. Among them, in mammalian cells, mitofusin 2 (Mfn2), located on both the outer mitochondrial membrane and the ER surface, has been proposed to be a physical tether between the two organelles, forming homotypic interactions and heterocomplexes with its homolog Mfn1. Recently, this widely accepted model has been challenged using quantitative EM analysis. Using a multiplicity of morphological, biochemical, functional, and genetic approaches, we demonstrate that Mfn2 ablation increases the structural and functional ER-mitochondria coupling. In particular, we show that in different cell types Mfn2 ablation or silencing increases the close contacts between the two organelles and strengthens the efficacy of inositol trisphosphate (IP3)-induced Ca 2+ transfer from the ER to mitochondria, sensitizing cells to a mitochondrial Ca 2+ overload-dependent death. We also show that the previously reported discrepancy between electron and fluorescence microscopy data on ER-mitochondria proximity in Mfn2-ablated cells is only apparent. By using a different type of morphological analysis of fluorescent images that takes into account (and corrects for) the gross modifications in mitochondrial shape resulting from Mfn2 ablation, we demonstrate that an increased proximity between the organelles is also observed by confocal microscopy when Mfn2 levels are reduced. Based on these results, we propose a new model for ER-mitochondria juxtaposition in which Mfn2 works as a tethering antagonist preventing an excessive, potentially toxic, proximity between the two organelles. mitofusin 2 | ER-mitochondria tethering | inter-organellar communication D uring the last decade, evidence has accumulated showing the existence of a continuous flux of information between the endoplasmic reticulum (ER) and mitochondria, two organelles whose privileged interplay is essential, e.g., for lipid metabolism and modulation of Ca 2+ signaling (1, 2). As to the former, Vance (3) firstly described a partially purified microsomal subfraction pulled down with mitochondria (fraction X, later renamed "mitochondria-associated membrane," MAM) that was found to be enriched in phosphatidylserine synthase and several enzymes involved in lipid and glucose metabolism, cholesterol, and ceramide biosynthesis (4, 5). As far as Ca 2+ signaling is concerned, the ERmitochondria axis plays a critical role in cell Ca 2+ homeostasis (6-8). In parallel, increases of Ca 2+ within mitochondria are essential in tuning physiological organelle activity (9, 10) and in modulating the process of cell death (6,8,11). ER-mitochondria connections and Ca 2+ signals are also critical for mitochondrial fission (12, 13), for autophagosome generation (14), and for the removal of damaged mitochondria by autophagy (15).Several proteins have been suggested to be ...

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Section: Mfn2 Ablation Does Not Alter the Dynamics Of Er-mitochondriamentioning

confidence: 95%

Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling

Filadi

Greotti

Turacchio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

486

432

View full text Add to dashboard Cite

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“…In response to UV irradiation, SERPINB3 protects cells through a directly inhibitory effect on mitogen-activated protein kinase (MAPK) family members JNK or p38 [85, 86]. SERPINB3 has also been found to localize to the mitochondrial inner membrane to interact with Complex I and suppress mitochondrial ROS generation [87]. …”

Section: Mechanisms Of Actionmentioning

confidence: 99%

SERPINB3 and B4: From biochemistry to biology

Sun

Sheshadri

Zong

2017

Seminars in Cell & Developmental Biology

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Human SERPINB3 and SERPINB4 are evolutionary duplicated serine/cysteine protease inhibitors. Genomic analysis indicates that these paralogous genes were encoded from independent loci arising from tandem gene duplication. Although the two molecules share 92% identity of their amino acid sequences, they are distinct in the Reactive Center Loop (RCL) including a hinge region and catalytic sequences which accounts for altered substrate specificity. Elevated expression of the two molecules have been reported to contribute to numerous pathological conditions such as inflammatory diseases and cancer. In this review, we focus on summarizing the biochemical features of SERPINB3/B4 and discussing the mechanistic basis for their biological functions and implications in human diseases.

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“…As a protease inhibitor, SERPINB3 is able to inhibit cysteine proteases (cathepsins L, S, K and papain) [10], and in cancer cells it confers resistance to drug-induced apoptosis by inhibiting lysosomal cathepsin proteases [23]. However, under a variety of stress conditions SERPINB3 displays an anti-apoptotic function unrelated to its proteinase inhibition activity [24, 25]. Indeed, SERPINB3 protects cells from exposure to radiation through an inhibitory effect either on the MAP family of c-Jun terminal kinase (JNK) [19] and the interaction between SERPINB3 and JNK1 was also supported by the crystallographic study [26]; or with a decreased phosphorylation of the proapoptotic p38 mitogen-activated protein kinase on p38 [27].…”

Section: Proteinmentioning

confidence: 99%

“…In addition, recent results, reported that SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I [25]. …”

Section: Proteinmentioning

confidence: 99%