bims-mecosi 2024-11-17 papers

Issue of 2024‒11‒17
five papers selected by
Verena Kohler, Umeå University

Cell Commun Signal. 2024 Nov 07. 22(1): 534

Inhibition of SGLT2 protects podocytes in diabetic kidney disease by rebalancing mitochondria-associated endoplasmic reticulum membranes.

Xuehong Li, Qiong Li, Xinying Jiang, Shicong Song, Wei Zou, Qinglan Yang, Sirui Liu, Shuangqin Chen, Cheng Wang.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the therapeutic landscape for diabetic kidney disease (DKD) patients, but their underlying mechanisms are complicated and not fully understood. Mitochondria-associated endoplasmic reticulum membranes (MAMs), the dynamic contact sites between mitochondria and the endoplasmic reticulum (ER), serve as intracellular platforms important for regulating cellular fate and function. This study explored the roles and mechanisms of SGLT2 inhibitors in regulating MAMs formation in diabetic podocytes.METHODS: We assessed MAMs formation in podocytes from DKD patients' renal biopsy samples and induced an increase in MAMs formation in cultured human podocytes by transfecting OMM-ER linker plasmid to investigate the effects of MAMs imbalance on podocyte injury. Empagliflozin-treated diabetic mice and podocyte-specific SGLT2 knockout diabetic mice (diabetic states were induced by streptozotocin and a high-fat diet), empagliflozin-treated podocytes, SGLT2-downregulated podocytes, and SGLT2-overexpressing podocytes were used to investigate the effects and mechanisms of SGLT2 inhibitors on MAMs formation in diabetic podocytes.
RESULTS: MAMs were increased in podocytes and were associated with renal dysfunction in DKD patients. Increased MAMs aggravated HG-induced podocyte injury. The expression of SGLT2 was increased in diabetic podocytes. In addition, empagliflozin-treatment and podocyte-specific SGLT2 knockout attenuated MAMs formation and podocyte injury in diabetic mice. Empagliflozin treatment and SGLT2 knockdown decreased podocyte MAMs formation by activating the AMP-activated protein kinase (AMPK) pathway, while SGLT2 overexpression had the opposite effect.
CONCLUSIONS: Inhibition of SGLT2 attenuates MAMs imbalance in diabetic podocytes by activating the AMPK pathway. This study expands our knowledge of the roles of SGLT2 inhibitors in improving DKD podocyte injury and provides new insights into DKD treatment.

Keywords: Diabetic kidney disease; Mitochondria-associated endoplasmic reticulum membranes; Podocyte; SGLT2 inhibitor

DOI: https://doi.org/10.1186/s12964-024-01914-1

Nat Commun. 2024 Nov 12. 15(1): 9775

Simultaneous detection of membrane contact dynamics and associated Ca2+ signals by reversible chemogenetic reporters.

Membrane contact sites (MCSs) are hubs allowing various cell organelles to coordinate their activities. The dynamic nature of these sites and their small size hinder analysis by current imaging techniques. To overcome these limitations, we here design a series of reversible chemogenetic reporters incorporating improved, low-affinity variants of splitFAST, and study the dynamics of different MCSs at high spatiotemporal resolution, both in vitro and in vivo. We demonstrate that these versatile reporters suit different experimental setups well, allowing one to address challenging biological questions. Using these probes, we identify a pathway in which calcium (Ca2+) signalling dynamically regulates endoplasmic reticulum-mitochondria juxtaposition, characterizing the underlying mechanism. Finally, by integrating Ca2+-sensing capabilities into the splitFAST technology, we introduce PRINCESS (PRobe for INterorganelle Ca2+-Exchange Sites based on SplitFAST), a class of reporters to simultaneously detect MCSs and measure the associated Ca2+ dynamics using a single biosensor.

DOI: https://doi.org/10.1038/s41467-024-52985-0

Cell Death Differ. 2024 Nov 13.

AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis.

Hao Liu, Shanliang Zheng, Guixue Hou, Junren Dai, Yanan Zhao, Fan Yang, Zhiyuan Xiang, Wenxin Zhang, Xingwen Wang, Yafan Gong, Li Li, Ning Zhang, Ying Hu.

Emerging evidence suggests that signaling pathways can be spatially regulated to ensure rapid and efficient responses to dynamically changing local cues. Ferroptosis is a recently defined form of lipid peroxidation-driven cell death. Although the molecular mechanisms underlying ferroptosis are emerging, spatial aspects of its signaling remain largely unexplored. By analyzing a public database, we found that a mitochondrial chaperone protein, glucose-regulated protein 75 (GRP75), may have a previously undefined role in regulating ferroptosis. This was subsequently validated. Interestingly, under ferroptotic conditions, GRP75 translocated from mitochondria to mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and the cytosol. Further mechanistic studies revealed a highly spatial regulation of GRP75-mediated antiferroptotic signaling. Under ferroptotic conditions, lipid peroxidation predominantly accumulated at the ER, which activated protein kinase A (PKA) in a cAMP-dependent manner. In particular, a signaling microdomain, the outer mitochondrial membrane protein A-kinase anchor protein 1 (AKAP1)-anchored PKA, phosphorylated GRP75 at S148 in MAMs. This caused GRP75 to be sequestered outside the mitochondria, where it competed with Nrf2 for Keap1 binding through a conserved high-affinity RGD-binding motif, ETGE. Nrf2 was then stabilized and activated, leading to the transcriptional activation of a panel of antiferroptotic genes. Blockade of the PKA/GRP75 axis dramatically increased the responses of cancer cells to ferroptosis both in vivo and in vitro. Our identification a localized signaling cascade involved in protecting cancer cells from ferroptosis broadens our understanding of cellular defense mechanisms against ferroptosis and also provides a new target axis (AKAP1/PKA/GRP75) to improve the responses of cancer cells to ferroptosis.

DOI: https://doi.org/10.1038/s41418-024-01414-2

Ecotoxicol Environ Saf. 2024 Nov 08. pii: S0147-6513(24)01383-6. [Epub ahead of print]287 117307

Selenium protects mouse spermatogonia against ivermectin-induced apoptosis by alleviating endoplasmic reticulum stress in vitro.

Daniel Chavez Varias, Sung-Hwan Moon, Seung Hee Shin, Buom-Yong Ryu.

Ivermectin (IVM) is a widely used anthelmintic in human and veterinary medicine. However, the increasing use of IVM raises concerns about its potential harm against non-targeted organisms. This study demonstrates a novel mechanism where IVM triggers apoptosis via endoplasmic reticulum (ER) stress in GC-1 spg in vitro. The inhibitory effects of selenium (Se) against the toxicological mechanism were also explored. IVM dose-dependently induces oxidative stress, dysregulated Ca2+ levels, and intracellular protein aggregation. Increased mitochondria-associated ER membrane (MAM) activity through Glucose-regulated Protein 75 (Grp75) overloads the mitochondria with Ca2+, causing mitochondrial dysfunction. These simultaneous stressors lead to unfolded protein response and apoptosis. Se reverses all these subcellular events by promoting the expression of selenoprotein-encoding genes to maintain the ER and redox homeostasis. The testis-enriched Glutathione Peroxidase 4 (Gpx4) and the testis-specific Selenoprotein V (Selenov) are only upregulated in the IVM and Se co-treatment group, suggesting their potential role in stress response. These findings confirm that toxic doses of IVM lead to programmed cell death in type B spermatogonia through redox imbalance-associated ER stress. This study provides valuable insights into refining male reproductive toxicity evaluation, targeting of ER stress to protect male germ cells, and maintaining male fertility from IVM-induced toxicity.

Keywords: Ivermectin; Male infertility; Redox Imbalance-associated Endoplasmic Reticulum (ER) Stress; Selenium

DOI: https://doi.org/10.1016/j.ecoenv.2024.117307

Liver Int. 2024 Nov 07.

Variants in MICOS10 Identified by Whole Genome Sequencing and RNA Sequencing in a New Type of Hepatocerebral Mitochondrial DNA Depletion Syndrome.

Yoshihito Kishita, Ayumu Sugiura, Nanako Omichi, Masaru Shimura, Yukiko Yatsuka, Kohta Nakamura, Toju Tanaka, Mitsuru Kubota, Kei Murayama, Akira Ohtake, Yasushi Okazaki.

BACKGROUND: The mitochondrial contact site and cristae organising system (MICOS) complex is required for cristae formation and is composed of seven proteins. Among the genes of MICOS complex, variants of MICOS13, IMMT and APOO have been reported to cause diseases.METHODS AND RESULTS: We report a case in which whole genome sequencing identified a variant of the MICOS10 gene associated with mitochondrial hepatopathy along with mitochondrial DNA depletion. We identified the deletion g.19596826_19601303del and the single nucleotide variant c.173G>C (p.Cys58Ser). The deletion including exon 1 might have caused complete loss of gene expression, indicating monoallelic expression from RNA sequencing. MIC10 was lost at the protein level in the patient's fibroblasts, and mitochondrial oxygen consumption was impaired. These were restored by overexpression of MICOS10 in the patient's fibroblasts.
CONCLUSION: Taken together, these findings indicate that MICOS10 is a causative gene for hepatopathy and neuropathy, a disease very similar to that associated with MICOS13.

Keywords: MICOS complex; RNA sequencing; hepatopathy; mitochondrial DNA; whole genome sequencing

DOI: https://doi.org/10.1111/liv.16148