bims-mecosi 2022-02-13 papers

Issue of 2022‒02‒13
six papers selected by
Verena Kohler

J Cell Sci. 2022 Feb 01. pii: jcs248534. [Epub ahead of print]135(3):

Endoplasmic reticulum-mitochondria signaling in neurons and neurodegenerative diseases.

Andrea Markovinovic, Jenny Greig, Sandra María Martín-Guerrero, Shaakir Salam, Sebastien Paillusson.

Recent advances have revealed common pathological changes in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis with related frontotemporal dementia (ALS/FTD). Many of these changes can be linked to alterations in endoplasmic reticulum (ER)-mitochondria signaling, including dysregulation of Ca2+ signaling, autophagy, lipid metabolism, ATP production, axonal transport, ER stress responses and synaptic dysfunction. ER-mitochondria signaling involves specialized regions of ER, called mitochondria-associated membranes (MAMs). Owing to their role in neurodegenerative processes, MAMs have gained attention as they appear to be associated with all the major neurodegenerative diseases. Furthermore, their specific role within neuronal maintenance is being revealed as mutant genes linked to major neurodegenerative diseases have been associated with damage to these specialized contacts. Several studies have now demonstrated that these specialized contacts regulate neuronal health and synaptic transmission, and that MAMs are damaged in patients with neurodegenerative diseases. This Review will focus on the role of MAMs and ER-mitochondria signaling within neurons and how damage of the ER-mitochondria axis leads to a disruption of vital processes causing eventual neurodegeneration.

Keywords: Endoplasmic reticulum; MAMs; Mitochondria; Neurodegenerative diseases; Neurons; Tethers

DOI: https://doi.org/10.1242/jcs.248534

Front Cell Dev Biol. 2022 ;10 826379

Low-Density Lipoprotein Internalization, Degradation and Receptor Recycling Along Membrane Contact Sites.

Mohammad Majharul Islam, Iryna Hlushchenko, Simon G Pfisterer.

Low-density lipoprotein (LDL) internalization, degradation, and receptor recycling is a fundamental process underlying hypercholesterolemia, a high blood cholesterol concentration, affecting more than 40% of the western population. Membrane contact sites influence endosomal dynamics, plasma membrane lipid composition, and cellular cholesterol distribution. However, if we focus on LDL-related trafficking events we mostly discuss them in an isolated fashion, without cellular context. It is our goal to change this perspective and to highlight that all steps from LDL internalization to receptor recycling are likely associated with dynamic membrane contact sites in which endosomes engage with the endoplasmic reticulum and other organelles.

Keywords: endosomal degradation; endosomal recycling; hypercholesterolemia; low-density lipoprotein (LDL); low-density lipoprotein receptor (LDLR); membrane contact site

DOI: https://doi.org/10.3389/fcell.2022.826379

Sci Transl Med. 2022 Feb 09. 14(631): eabh3763

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models.

Lucie Crouzier, Alberto Danese, Yuko Yasui, Elodie M Richard, Jean-Charles Liévens, Simone Patergnani, Simon Couly, Camille Diez, Morgane Denus, Nicolas Cubedo, Mireille Rossel, Marc Thiry, Tsung-Ping Su, Paolo Pinton, Tangui Maurice, Benjamin Delprat.

The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences; currently, no treatment is available. The disease is caused by mutations in the WSF1 gene, coding for the protein wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed as mitochondria-associated ER membranes (MAMs). Inherited mutations usually reduce the protein's stability, altering its homeostasis and ultimately reducing ER to mitochondria calcium ion transfer, leading to mitochondrial dysfunction and cell death. In this study, we found that activation of the sigma-1 receptor (S1R), an ER-resident protein involved in calcium ion transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored calcium ion transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in zebrafish and mouse models of the disease. Our findings provide a potential therapeutic strategy for treating Wolfram syndrome by efficiently boosting MAM function using the ligand-operated S1R chaperone. Moreover, such strategy might also be relevant for other degenerative and mitochondrial diseases involving MAM dysfunction.

DOI: https://doi.org/10.1126/scitranslmed.abh3763

Chem Biol Interact. 2022 Feb 04. pii: S0009-2797(22)00049-7. [Epub ahead of print]354 109844

Perfluorooctanoic acid induces hepatocellular endoplasmic reticulum stress and mitochondrial-mediated apoptosis in vitro via endoplasmic reticulum-mitochondria communication.

Qian Wang, Wenying Chen, Boyang Zhang, Zilu Gao, Qipeng Zhang, Huiqiong Deng, Lingyun Han, Xiao Li Shen.

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant that is widely distributed in the natural environment. Cohort study showed that PFOA-producing workers displayed a significant increase for mortality of liver cancer and liver cirrhosis. However, the underlying mechanism of PFOA-induced hepatotoxicity is far from clear. In this research, cell viability, apoptosis rate, reactive oxygen species, mitochondrial membrane potential (ΔΨm), calcium ion levels, and protein expressions of human liver L02 cells in response to PFOA were determined. Results indicated that a 24 h-treatment with 64 and 256 μM PFOA could remarkably induce mitochondrial-mediated apoptosis via initiating the vicious cycle between endoplasmic reticulum stress and oxidative stress, thereby increasing the level of calcium ion and decreasing the level of ΔΨm, simultaneously elevating the protein expressions of Cyclophilin D (CYPD), Bcl-2 homologous antagonist/killer (Bak), Bcl-2-associated X protein (Bax), Bcl-2-like protein 11 (Bim), cytochrome C (Cyt-C), 78 kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), and thioredoxin-interacting protein (TXNIP), while inhibiting the protein expression of tumor necrosis factor receptor-associated protein 1 (TRAP1), Lon protease 1 (Lonp1), Pro-caspase-9, B-cell lymphoma-2 (Bcl-2), and Sigma 1-type opioid receptor (Sig-1R) (p < 0.05). To sum up, PFOA-induced hepatocellular endoplasmic reticulum stress and mitochondrial-mediated apoptosis in vitro was regulated by endoplasmic reticulum (ER)-mitochondria communication via mitochondria-associated ER membranes (MAMs).

Keywords: Apoptosis; ER-Mitochondria communication; Mitochondria-associated ER membranes; Perfluorooctanoic acid; Persistent organic pollutant

DOI: https://doi.org/10.1016/j.cbi.2022.109844

Diabetes. 2022 Feb 08. pii: db210983. [Epub ahead of print]

PACS-2 Ameliorates Tubular Injury by Facilitating Endoplasmic Reticulum-Mitochondria Contact and Mitophagy in Diabetic Nephropathy.

Mitochondria-associated endoplasmic reticulum membrane (MAM) is emerging as a novel insight into tubular injury in diabetic nephropathy (DN), but the precise mechanism remains unclear. Here, we demonstrate that the expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a critical regulator of MAM formation, is significantly decreased in renal tubules of patients with DN, which is positively correlated with renal function and negatively correlated with degrees of tubulointerstitial lesions. Conditional deletion of Pacs-2 in proximal tubules (PT) aggravates albuminuria and tubular injury in streptozotocin (STZ)-induced diabetic mice. Mitochondrial fragmentation, MAM disruption and defective mitophagy accompanied by altered expression of mitochondrial dynamics and mitophagic protein including DRP1 and BECN1 are observed in tubules from diabetic mice, while these changes are more pronounced in PT-specific Pacs-2 knockout mice. In vitro, overexpression of PACS-2 in HK-2 cells alleviates excessive mitochondrial fission induced by high glucose through blocking mitochondrial recruitment of DRP1, and subsequently restores MAM integrity and enhances mitophagy. Mechanistically, PACS-2 binds to BECN1 and mediates the relocalization of BECN1 to MAM where it promotes the formation of mitophagosome. Together, these data highlight an important but previously unrecognized role of PACS-2 in ameliorating tubular injury in DN by facilitating MAM formation and mitophagy.

DOI: https://doi.org/10.2337/db21-0983