bims-mecmid 2022-01-09 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2022‒01‒09
seven papers selected by
Mauricio Cardenas Rodriguez
University of Padova

Neuraminidase1 Inhibitor Protects Against Doxorubicin-Induced Cardiotoxicity via Suppressing Drp1-Dependent Mitophagy.
A Glucagon-like Peptide 1 Analogue Protects Mitochondria and Attenuates Hypoxia-reoxygenation Injury in Cultured Cardiomyocytes.
Drp1 SUMO/deSUMOylation by Senp5 isoforms influences ER tubulation and mitochondrial dynamics to regulate brain development.
Increased mitochondrial fission drives the reprogramming of fatty acid metabolism in hepatocellular carcinoma cells through suppression of Sirtuin 1.
Keratins modulate cellular redox homeostasis and mitochondrial dynamics.
The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1.
Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway.

Front Cell Dev Biol. 2021 ;9 802502

Neuraminidase1 Inhibitor Protects Against Doxorubicin-Induced Cardiotoxicity via Suppressing Drp1-Dependent Mitophagy.

Yating Qin, Chao Lv, Xinxin Zhang, Weibin Ruan, Xiangyu Xu, Chen Chen, Xinyun Ji, Li Lu, Xiaomei Guo.

  Anthracyclines, such as doxorubicin (DOX), are among the effective chemotherapeutic drugs for various malignancies. However, their clinical use is limited by irreversible cardiotoxicity. This study sought to determine the role of neuraminidase 1 (NEU1) in DOX-induced cardiomyopathy and the potential cardio-protective effects of NEU1 inhibitor oseltamivir (OSE). Male Sprague-Dawley (SD) rats were randomized into three groups: control, DOX, and DOX + OSE. NEU1 was highly expressed in DOX-treated rat heart tissues compared with the control group, which was suppressed by OSE administration. Rats in the DOX + OSE group showed preserved cardiac function and were protected from DOX-induced cardiomyopathy. The beneficial effects of OSE were associated with the suppression of dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and mitophagy. In detail, the elevated NEU1 in cardiomyocytes triggered by DOX increased the expression of Drp1, which subsequently enhanced mitochondrial fission and PINK1/Parkin pathway-mediated mitophagy, leading to a maladaptive feedback circle towards myocardial apoptosis and cell death. OSE administration selectively inhibited the increased NEU1 in myocardial cells insulted by DOX, followed by reduction of Drp1 expression, inhibition of PINK1 stabilization on mitochondria, and Parkin translocation to mitochondria, thus alleviating excessive mitochondrial fission and mitophagy, alleviating subsequent development of cellular apoptotic process. This work identified NEU1 as a crucial inducer of DOX-induced cardiomyopathy by promoting Drp1-dependent mitochondrial fission and mitophagy, and NEU1 inhibitor showed new indications of cardio-protection against DOX cardiotoxicity.

Keywords:  cardiotoxicity; doxorubicin; dynamin-related protein 1 (Drp1); mitophagy; neuraminidase1; oseltamivir

DOI:  https://doi.org/10.3389/fcell.2021.802502
J Cardiovasc Pharmacol. 2021 Dec 31.

A Glucagon-like Peptide 1 Analogue Protects Mitochondria and Attenuates Hypoxia-reoxygenation Injury in Cultured Cardiomyocytes.

Miyuki Kobara, Hiroe Toba, Tetsuo Nakata.

ABSTRACT: Glucagon-like peptide 1 (GLP-1) analogues improve glycemic control in diabetes and protect the heart against ischemia-reperfusion injury. However, the mechanisms underlying this protection remain unclear. Mitochondria are essential for myocyte homeostasis. Therefore, we herein examined the effects of a GLP-1 analogue on mitochondria after the hypoxia-reoxygenation of rat neonatal cultured cardiomyocytes. Cardiomyocytes were subjected to hypoxia for 5 hours followed by reoxygenation for 30 minutes in the presence or absence of exendin 4 (50 nmol/L), a GLP-1 analogue. Hypoxia-reoxygenation increased lactate dehydrogenase and caspase-3 activities, indicators of lethal myocyte injury and apoptosis, respectively, and exendin 4 attenuated these increases. The content of ATP in myocytes decreased after hypoxia-reoxygenation, but was preserved by exendin 4. The membrane potential and shape of mitochondria were assessed using a fluorescent probe. Exendin 4 attenuated the hypoxia-reoxygenation-induced disruption of the mitochondrial membrane potential and shortening. Mitochondrial quality control-related factors, such as optic atrophy protein 1 (OPA1), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and parkin, were examined by Western blotting. Exendin 4 significantly increased the expression of the fusion proteins, OPA1 and Mfn2, and decreased that of the mitophagy-related protein, parkin, without altering Drp1 expression levels. Exendin 4 also preserved Akt phosphorylation levels after hypoxia-reoxygenation, while wortmannin, an inhibitor of the PI3K-Akt pathway, blunted exendin 4-induced myocyte protection and its effects on mitochondrial quality control factors. In conclusion, exendin 4 protected mitochondria by preserving the phosphorylation of Akt and fusion proteins, leading to the attenuation of hypoxia-reoxygenation-induced injury in cultured myocytes.

DOI: https://doi.org/10.1097/FJC.0000000000001218
iScience. 2021 Dec 17. 24(12): 103484

Drp1 SUMO/deSUMOylation by Senp5 isoforms influences ER tubulation and mitochondrial dynamics to regulate brain development.

Seiya Yamada, Ayaka Sato, Naotada Ishihara, Hiroki Akiyama, Shin-Ichi Sakakibara.

  Brain development is a highly orchestrated process requiring spatiotemporally regulated mitochondrial dynamics. Drp1, a key molecule in the mitochondrial fission machinery, undergoes various post-translational modifications including conjugation to the small ubiquitin-like modifier (SUMO). However, the functional significance of SUMOylation/deSUMOylation on Drp1 remains controversial. SUMO-specific protease 5 (Senp5L) catalyzes the deSUMOylation of Drp1. We revealed that a splicing variant of Senp5L, Senp5S, which lacks peptidase activity, prevents deSUMOylation of Drp1 by competing against other Senps. The altered SUMOylation level of Drp1 induced by Senp5L/5S affects mitochondrial morphology probably through controlling Drp1 ubiquitination and tubulation of the endoplasmic reticulum. A dynamic SUMOylation/deSUMOylation balance controls neuronal polarization and migration during the development of the cerebral cortex. These findings suggest a novel role of post-translational modification, in which deSUMOylation enzyme isoforms competitively regulate mitochondrial dynamics via Drp1 SUMOylation levels, in a tightly controlled process of neuronal differentiation and corticogenesis.

Keywords:  Cellular neuroscience; Molecular neuroscience; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2021.103484
Cancer Commun (Lond). 2022 Jan 04.

Increased mitochondrial fission drives the reprogramming of fatty acid metabolism in hepatocellular carcinoma cells through suppression of Sirtuin 1.

Dan Wu, Yi Yang, Yiran Hou, Zifeng Zhao, Ning Liang, Peng Yuan, Tao Yang, Jinliang Xing, Jibin Li.

  BACKGROUND: Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes. Recently, abnormally increased mitochondrial fission has been observed in several types of cancer. However, the functional roles of increased mitochondrial fission in lipid metabolism reprogramming in cancer cells remain unclear. This study aimed to explore the role of increased mitochondrial fission in lipid metabolism in hepatocellular carcinoma (HCC) cells.METHODS: Lipid metabolism was determined by evaluating the changes in the expressions of core lipid metabolic enzymes and intracellular lipid content. The rate of fatty acid oxidation was evaluated by [3 H]-labelled oleic acid. The mitochondrial morphology in HCC cells was evaluated by fluorescent staining. The expression of protein was determined by real-time PCR, iimmunohistochemistry and Western blotting.
RESULTS: Activation of mitochondrial fission significantly promoted de novo fatty acid synthesis in HCC cells through upregulating the expression of lipogenic genes fatty acid synthase (FASN), acetyl-CoA carboxylase1 (ACC1), and elongation of very long chain fatty acid protein 6 (ELOVL6), while suppressed fatty acid oxidation by downregulating carnitine palmitoyl transferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1). Consistently, suppressed mitochondrial fission exhibited the opposite effects. Moreover, in vitro and in vivo studies revealed that mitochondrial fission-induced lipid metabolism reprogramming significantly promoted the proliferation and metastasis of HCC cells. Mechanistically, mitochondrial fission increased the acetylation level of sterol regulatory element-binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) by suppressing nicotinamide adenine dinucleotide (NAD+)/Sirtuin 1 (SIRT1) signaling. The elevated SREBP1 then upregulated the expression of FASN, ACC1 and ELOVL6 in HCC cells, while PGC-1α/PPARα suppressed the expression of CPT1A and ACOX1.
CONCLUSIONS: Increased mitochondrial fission plays a crucial role in the reprogramming of lipid metabolism in HCC cells, which provides strong evidence for the use of this process as a drug target in the treatment of this malignancy.

Keywords:  Sirtuin 1; fatty acid oxidation; hepatocellular carcinoma; lipogenesis; metabolic reprogramming; mitochondrial fission

DOI:  https://doi.org/10.1002/cac2.12247
J Invest Dermatol. 2021 Dec 30. pii: S0022-202X(21)02687-7. [Epub ahead of print]

Keratins modulate cellular redox homeostasis and mitochondrial dynamics.

Alyssa Vetter, Laura-Sophie Beier, Jamal-Eddine Bouameur, Thomas M Magin.



Keywords:  Drp1; keratinocytes; keratins; mitochondria; redox homeostasis

DOI:  https://doi.org/10.1016/j.jid.2021.12.025
EMBO Rep. 2022 Jan 07. e48754

The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1.

Emily Waters, Kevin A Wilkinson, Amy L Harding, Ruth E Carmichael, Darren Robinson, Helen E Colley, Chun Guo.

  Mitochondria are unavoidably subject to organellar stress resulting from exposure to a range of reactive molecular species. Consequently, cells operate a poorly understood quality control programme of mitophagy to facilitate elimination of dysfunctional mitochondria. Here, we used a model stressor, deferiprone (DFP), to investigate the molecular basis for stress-induced mitophagy. We show that mitochondrial fission 1 protein (Fis1) is required for DFP-induced mitophagy and that Fis1 is SUMOylated at K149, an amino acid residue critical for Fis1 mitochondrial localization. We find that DFP treatment leads to the stabilization of the SUMO protease SENP3, which is mediated by downregulation of the E3 ubiquitin (Ub) ligase CHIP. SENP3 is responsible for Fis1 deSUMOylation and depletion of SENP3 abolishes DFP-induced mitophagy. Furthermore, preventing Fis1 SUMOylation by conservative K149R mutation enhances Fis1 mitochondrial localization. Critically, expressing a Fis1 K149R mutant restores DFP-induced mitophagy in SENP3-depleted cells. Thus, we propose a model in which SENP3-mediated deSUMOylation facilitates Fis1 mitochondrial localization to underpin stress-induced mitophagy.

Keywords:  Fis1; SENP3; SUMO; mitophagy; organellar stress

DOI:  https://doi.org/10.15252/embr.201948754
Front Cell Dev Biol. 2021 ;9 769213

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway.

Yun Cao, Zhaowei Chen, Jijia Hu, Jun Feng, Zijing Zhu, Yanqin Fan, Qiaoxuan Lin, Guohua Ding.

  The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.

Keywords:  DKD; ER stress; MAMs; Mfn2; apoptosis; podocyte

DOI:  https://doi.org/10.3389/fcell.2021.769213