bims-mecosi 2022-08-28 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2022‒08‒28
nine papers selected by
Verena Kohler

STIM Proteins and Regulation of SOCE in ER-PM Junctions.
Retraction: High glucose activated cardiac fibroblasts by a disruption of mitochondria-associated membranes.
A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane.
Structure-function analysis of the ER-peroxisome contact site protein Pex32.
Retraction: Mitofusin-2 enhances mitochondrial contact with the endoplasmic reticulum and promotes diabetic cardiomyopathy.
Cdk5 regulates IP3R1-mediated Ca2+ dynamics and Ca2+-mediated cell proliferation.
Intermittent Hypoxia-Induced Cardiomyocyte Death Is Mediated by HIF-1 Dependent MAM Disruption.
Mitochondria-lysosome crosstalk in GBA1-associated Parkinson's disease.
A pro-tumorigenic mDia2-MIRO1 axis controls mitochondrial positioning and function in cancer-associated fibroblasts.

Biomolecules. 2022 Aug 20. pii: 1152. [Epub ahead of print]12(8):

STIM Proteins and Regulation of SOCE in ER-PM Junctions.

Moaz Ahmad, Sasirekha Narayanasamy, Hwei Ling Ong, Indu Ambudkar.

  ER-PM junctions are membrane contact sites formed by the endoplasmic reticulum (ER) and plasma membrane (PM) in close apposition together. The formation and stability of these junctions are dependent on constitutive and dynamic enrichment of proteins, which either contribute to junctional stability or modulate the lipid levels of both ER and plasma membranes. The ER-PM junctions have come under much scrutiny recently as they serve as hubs for assembling the Ca2+ signaling complexes. This review summarizes: (1) key findings that underlie the abilities of STIM proteins to accumulate in ER-PM junctions; (2) the modulation of Orai/STIM complexes by other components found within the same junction; and (3) how Orai1 channel activation is coordinated and coupled with downstream signaling pathways.

Keywords:  ER-PM junctions; Orai1; SOCE; STIM; calcium signaling; phospholipids

DOI:  https://doi.org/10.3390/biom12081152
Front Physiol. 2022 ;13 1006459

Retraction: High glucose activated cardiac fibroblasts by a disruption of mitochondria-associated membranes.

Frontiers Editorial Office

[This retracts the article DOI: 10.3389/fphys.2021.724470.].

DOI: https://doi.org/10.3389/fphys.2022.1006459
Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2205425119

A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane.

Andrés Guillén-Samander, Yumei Wu, S Sebastian Pineda, Francisco J García, Julia N Eisen, Marianna Leonzino, Berrak Ugur, Manolis Kellis, Myriam Heiman, Pietro De Camilli.

  Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of plasma membrane (PM) lipid scramblases whose action results in exposure of PtdSer at the cell surface. VPS13A is an endoplasmic reticulum (ER)-anchored lipid transfer protein with a putative role in the transport of lipids at contacts of the ER with other membranes. Recently VPS13A and XK were reported to interact by still unknown mechanisms. So far, however, there is no evidence for a colocalization of the two proteins at contacts of the ER with the PM, where XK resides, as VPS13A was shown to be localized at contacts between the ER and either mitochondria or lipid droplets. Here we show that VPS13A can also localize at ER-PM contacts via the binding of its PH domain to a cytosolic loop of XK, that such interaction is regulated by an intramolecular interaction within XK, and that both VPS13A and XK are highly expressed in the caudate neurons. Binding of the PH domain of VPS13A to XK is competitive with its binding to intracellular membranes that mediate other tethering functions of VPS13A. Our findings support a model according to which VPS13A-dependent lipid transfer between the ER and the PM is coupled to lipid scrambling within the PM. They raise the possibility that defective cell surface exposure of PtdSer may be responsible for neurodegeneration.

Keywords:  VPS13B; VPS13C; VPS13D; chorein; junctophilin

DOI:  https://doi.org/10.1073/pnas.2205425119
Front Cell Dev Biol. 2022 ;10 957871

Structure-function analysis of the ER-peroxisome contact site protein Pex32.

Fei Wu, Ida J van der Klei.

  In the yeast Hansenula polymorpha, the ER protein Pex32 is required for associating peroxisomes to the ER. Here, we report on a structure-function analysis of Pex32. Localization studies of various Pex32 truncations showed that the N-terminal transmembrane domain of Pex32 is responsible for sorting. Moreover, this part of the protein is sufficient for the function of Pex32 in peroxisome biogenesis. The C-terminal DysF domain is required for concentrating Pex32 at ER-peroxisome contact sites and has the ability to bind to peroxisomes. In order to better understand the role of Pex32 in peroxisome biogenesis, we analyzed various peroxisomal proteins in pex32 cells. This revealed that Pex11 levels are strongly reduced in pex32 cells. This may explain the strong reduction in peroxisome numbers in pex32 cells, which also occurs in cells lacking Pex11.

Keywords:  PEX11; contact site; endoplasmic reticulum; peroxisome; pex32

DOI:  https://doi.org/10.3389/fcell.2022.957871
Front Physiol. 2022 ;13 1006583

Retraction: Mitofusin-2 enhances mitochondrial contact with the endoplasmic reticulum and promotes diabetic cardiomyopathy.

Frontiers Editorial Office

[This retracts the article DOI: 10.3389/fphys.2021.707634.].

DOI: https://doi.org/10.3389/fphys.2022.1006583
Cell Mol Life Sci. 2022 Aug 24. 79(9): 495

Cdk5 regulates IP3R1-mediated Ca2+ dynamics and Ca2+-mediated cell proliferation.

Saranya NavaneethaKrishnan, Vincent Law, Jungkwon Lee, Jesusa L Rosales, Ki-Young Lee.

  Loss of cyclin-dependent kinase 5 (Cdk5) in the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) increases ER-mitochondria tethering and ER Ca2+ transfer to the mitochondria, subsequently increasing mitochondrial Ca2+ concentration ([Ca2+]mt). This suggests a role for Cdk5 in regulating intracellular Ca2+ dynamics, but how Cdk5 is involved in this process remains to be explored. Using ex vivo primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5-/- mouse embryos, we show here that loss of Cdk5 causes an increase in cytosolic Ca2+concentration ([Ca2+]cyt), which is not due to reduced internal Ca2+ store capacity or increased Ca2+ influx from the extracellular milieu. Instead, by stimulation with ATP that mediates release of Ca2+ from internal stores, we determined that the rise in [Ca2+]cyt in Cdk5-/- MEFs is due to increased inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release from internal stores. Cdk5 interacts with the IP3R1 Ca2+ channel and phosphorylates it at Ser421. Such phosphorylation controls IP3R1-mediated Ca2+ release as loss of Cdk5, and thus, loss of IP3R1 Ser421 phosphorylation triggers an increase in IP3R1-mediated Ca2+ release in Cdk5-/- MEFs, resulting in elevated [Ca2+]cyt. Elevated [Ca2+]cyt in these cells further induces the production of reactive oxygen species (ROS), which upregulates the levels of Nrf2 and its targets, Prx1 and Prx2. Cdk5-/- MEFs, which have elevated [Ca2+]cyt, proliferate at a faster rate compared to wt, and Cdk5-/- embryos have increased body weight and size compared to their wt littermates. Taken together, we show that altered IP3R1-mediated Ca2+ dynamics due to Cdk5 loss correspond to accelerated cell proliferation that correlates with increased body weight and size in Cdk5-/- embryos.

Keywords:  Ca2+ signaling; Cdk5; IP3R; Proliferation

DOI:  https://doi.org/10.1007/s00018-022-04515-8
Antioxidants (Basel). 2022 Jul 27. pii: 1462. [Epub ahead of print]11(8):

Intermittent Hypoxia-Induced Cardiomyocyte Death Is Mediated by HIF-1 Dependent MAM Disruption.

Sophie Moulin, Amandine Thomas, Stefan Wagner, Michael Arzt, Hervé Dubouchaud, Frédéric Lamarche, Sophie Bouyon, Guillaume Vial, Diane Godin-Ribuot, Jean-Louis Pépin, Claire Arnaud, Elise Belaidi.

  RATIONALE: Intermittent hypoxia (IH) is one of the main features of sleep-disordered breathing (SDB). Recent findings indicate that hypoxia inducible factor-1 (HIF-1) promotes cardiomyocytes apoptosis during chronic IH, but the mechanisms involved remain to be elucidated. Here, we hypothesize that IH-induced ER stress is associated with mitochondria-associated ER membrane (MAM) alteration and mitochondrial dysfunction, through HIF-1 activation.METHODS: Right atrial appendage biopsies from patients with and without SDB were used to determine HIF-1α, Grp78 and CHOP expressions. Wild-type and HIF-1α+/- mice were exposed to normoxia (N) or IH (21-5% O2, 60 cycles/h, 8 h/day) for 21 days. Expressions of HIF-1α, Grp78 and CHOP, and apoptosis, were measured by Western blot and immunochemistry. In isolated cardiomyocytes, we examined structural integrity of MAM by proximity ligation assay and their function by measuring ER-to-mitochondria Ca2+ transfer by confocal microscopy. Finally, we measured mitochondrial respiration using oxygraphy and calcium retention capacity (CRC) by spectrofluorometry. MAM structure was also investigated in H9C2 cells incubated with 1 mM CoCl2, a potent HIF-1α inducer.
RESULTS: In human atrial biopsies and mice, IH induced HIF-1 activation, ER stress and apoptosis. IH disrupted MAM, altered Ca2+ homeostasis, mitochondrial respiration and CRC. Importantly, IH had no effect in HIF-1α+/- mice. Similar to what observed under IH, HIF-1α overexpression was associated with MAM alteration in H9C2.
CONCLUSION: IH-induced ER stress, MAM alterations and mitochondrial dysfunction were mediated by HIF-1; all these intermediate mechanisms ultimately inducing cardiomyocyte apoptosis. This suggests that HIF-1 modulation might limit the deleterious cardiac effects of SDB.

Keywords:  cardiomyocyte death; hypoxia inducible factor-1; intermittent hypoxia; mitochondria associated-ER membrane; sleep disordered breathing

DOI:  https://doi.org/10.3390/antiox11081462
3 Biotech. 2022 Sep;12(9): 230

Mitochondria-lysosome crosstalk in GBA1-associated Parkinson's disease.

M Sahyadri, Abhishek P R Nadiga, Seema Mehdi, K Mruthunjaya, Pawan G Nayak, Vipan K Parihar, S N Manjula.

  Organelle crosstalk is significant in regulating their respective functions and subsequent cell fate. Mitochondria and lysosomes are amongst the essential organelles in maintaining cellular homeostasis. Mitochondria-lysosome connections, which may develop dynamically in the human neurons, have been identified as sites of bidirectional communication. Aberrancies are often associated with neurodegenerative disorders like Parkinson's disease (PD), suggesting the physical and functional link between these two organelles. PD is often linked with genetic mutations of several mutations discovered in the familial forms of the disease; some are considered risk factors. Many of these genes are either associated with mitochondrial function or belong to endo-lysosomal pathways. The recent investigations have indicated that neurons with mutant glucosylceramidase beta (GBA1) exhibit extended mitochondria-lysosome connections in individuals with PD. This may be due to impaired control of the untethering protein, which aids in the hydrolysis of Rab7 GTP required for contact untethering. A GCase modulator may be used to augment the reduced GBA1 lysosomal enzyme activity in the neurons of PD patients. This review focuses on how GBA1 mutation in PD is interlinked with mitochondria-lysosome (ML) crosstalk, exploring the pathways governing these interactions and mechanistically comprehending the mitochondrial and lysosomal miscommunication in the pathophysiology of PD. This review is based on the limited literature available on the topic and hence may be subject to bias in its views. Our estimates may be conservative and limited due to the lack of studies under the said discipline due to its inherent complex nature. The current association of GBA1 to PD pathogenesis is based on the limited scope of study and further research is necessary to explore the risk factors further and identify the relationship with more detail.

Keywords:  Glucosylceramidase Beta (GBA); Lysosome; ML crosstalk; Mitochondria; Neuronal dysfunction; Parkinson's disease

DOI:  https://doi.org/10.1007/s13205-022-03261-9
Cancer Res. 2022 Aug 23. pii: CAN-22-0162. [Epub ahead of print]

A pro-tumorigenic mDia2-MIRO1 axis controls mitochondrial positioning and function in cancer-associated fibroblasts.

Michael Cangkrama, Huan Liu, James Whipman, Maria Zubair, Mai Matsushita, Michela Di Filippo, Manfred Kopf, Metello Innocenti, Sabine Werner.

Cancer-associated fibroblasts (CAF) are key regulators of tumorigenesis. Further insights into the tumor promoting mechanisms of action of CAFs could help improve cancer diagnosis and treatment. Here we show that the formin mDia2 regulates the positioning and function of mitochondria in dermal fibroblasts, thereby promoting a pro-tumorigenic CAF phenotype. Mechanistically, mDia2 stabilized the mitochondrial trafficking protein MIRO1. Loss of mDia2 or MIRO1 in fibroblasts or CAFs reduced the presence of mitochondria and ATP levels near the plasma membrane and at CAF-tumor cell contact sites, caused metabolic alterations characteristic of mitochondrial dysfunction, and suppressed the secretion of pro-tumorigenic proteins. In mouse models of squamous carcinogenesis, genetic or pharmacological inhibition of mDia2, MIRO1, or their common upstream regulator activin A inhibited tumor formation. Consistently, co-upregulation of mDia2 and MIRO1 in the stroma of various human cancers negatively correlated with survival. This work unveils a key role of mitochondria in the pro-tumorigenic CAF phenotype and identifies an activin A/mDia2/MIRO1 signaling axis in CAFs with diagnostic and therapeutic potential.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0162