bims-mecosi 2023-05-07 papers

Issue of 2023‒05‒07
four papers selected by
Verena Kohler

Cell Calcium. 2023 Apr 25. pii: S0143-4160(23)00055-6. [Epub ahead of print]112 102743

The ER-mitochondria interface, where Ca2+ and cell death meet.

Ian de Ridder, Martijn Kerkhofs, Fernanda O Lemos, Jens Loncke, Geert Bultynck, Jan B Parys.

Endoplasmic reticulum (ER)-mitochondria contact sites are crucial to allow Ca2+ flux between them and a plethora of proteins participate in tethering both organelles together. Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a pivotal role at such contact sites, participating in both ER-mitochondria tethering and as Ca2+-transport system that delivers Ca2+ from the ER towards mitochondria. At the ER-mitochondria contact sites, the IP3Rs function as a multi-protein complex linked to the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane, via the chaperone glucose-regulated protein 75 (GRP75). This IP3R-GRP75-VDAC1 complex supports the efficient transfer of Ca2+ from the ER into the mitochondrial intermembrane space, from which the Ca2+ ions can reach the mitochondrial matrix through the mitochondrial calcium uniporter. Under physiological conditions, basal Ca2+ oscillations deliver Ca2+ to the mitochondrial matrix, thereby stimulating mitochondrial oxidative metabolism. However, when mitochondrial Ca2+ overload occurs, the increase in [Ca2+] will induce the opening of the mitochondrial permeability transition pore, thereby provoking cell death. The IP3R-GRP75-VDAC1 complex forms a hub for several other proteins that stabilize the complex and/or regulate the complex's ability to channel Ca2+ into the mitochondria. These proteins and their mechanisms of action are discussed in the present review with special attention for their role in pathological conditions and potential implication for therapeutic strategies.

Keywords: Apoptosis; ER-mitochondria tether; IP(3) receptor; Metabolism; Mitochondria-associated membranes

DOI: https://doi.org/10.1016/j.ceca.2023.102743

Biol Chem. 2023 May 05.

Autophagic and non-autophagic functions of the Saccharomyces cerevisiae PROPPINs Atg18, Atg21 and Hsv2.

Lisa Marquardt, Michael Thumm.

Atg18, Atg21 and Hsv2 are homologous β-propeller proteins binding to PI3P and PI(3,5)P2. Atg18 is thought to organize lipid transferring protein complexes at contact sites of the growing autophagosome (phagophore) with both the ER and the vacuole. Atg21 is restricted to the vacuole phagophore contact, where it organizes part of the Atg8-lipidation machinery. The role of Hsv2 is less understood, it partly affects micronucleophagy. Atg18 is further involved in regulation of PI(3,5)P2 synthesis. Recently, a novel Atg18-retromer complex and its role in vacuole homeostasis and membrane fission was uncovered.

Keywords: PtdIns3P; autophagosome biogenesis; membrane fission; retromer; vacuole fragmentation

DOI: https://doi.org/10.1515/hsz-2023-0126

Front Cell Dev Biol. 2023 ;11 1161910

Bok: real killer or bystander with non-apoptotic roles?

Caden G Bonzerato, Richard J H Wojcikiewicz.

Bcl-2-related ovarian killer, Bok, was first labeled "pro-apoptotic" due to its ability to cause cell death when over-expressed. However, it has become apparent that this is not a good name, since Bok is widely expressed in tissues other than ovaries. Further, there is serious doubt as to whether Bok is a real "killer," due to disparities in the ability of over-expressed versus endogenous Bok to trigger apoptosis. In this brief review, we rationalize these disparities and argue that endogenous Bok is very different from the pro-apoptotic, mitochondrial outer membrane permeabilization mediators, Bak and Bax. Instead, Bok is a stable, endoplasmic reticulum-located protein bound to inositol 1,4,5 trisphosphate receptors. From this location, Bok plays a variety of roles, including regulation of endoplasmic reticulum/mitochondria contact sites and mitochondrial dynamics. Therefore, categorizing Bok as a "killer" may well be misleading and instead, endogenous Bok would better be considered an endoplasmic reticulum-located "bystander", with non-apoptotic roles.

Keywords: Bcl-2 related ovarian killer; apoptosis; inositol 1 4 5-trisphosphate receptor; mitochondria-associated ER membranes; mitochondrial dynamics; myeloid-cell leukemia 1; ubiquitin-proteasome pathway

DOI: https://doi.org/10.3389/fcell.2023.1161910

Cell Death Dis. 2023 04 29. 14(4): 297

Perturbation of the host cell Ca2+ homeostasis and ER-mitochondria contact sites by the SARS-CoV-2 structural proteins E and M.

Elena Poggio, Francesca Vallese, Andreas J W Hartel, Travis J Morgenstern, Scott A Kanner, Oliver Rauh, Flavia Giamogante, Lucia Barazzuol, Kenneth L Shepard, Henry M Colecraft, Oliver Biggs Clarke, Marisa Brini, Tito Calì.

Coronavirus disease (COVID-19) is a contagious respiratory disease caused by the SARS-CoV-2 virus. The clinical phenotypes are variable, ranging from spontaneous recovery to serious illness and death. On March 2020, a global COVID-19 pandemic was declared by the World Health Organization (WHO). As of February 2023, almost 670 million cases and 6,8 million deaths have been confirmed worldwide. Coronaviruses, including SARS-CoV-2, contain a single-stranded RNA genome enclosed in a viral capsid consisting of four structural proteins: the nucleocapsid (N) protein, in the ribonucleoprotein core, the spike (S) protein, the envelope (E) protein, and the membrane (M) protein, embedded in the surface envelope. In particular, the E protein is a poorly characterized viroporin with high identity amongst all the β-coronaviruses (SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43) and a low mutation rate. Here, we focused our attention on the study of SARS-CoV-2 E and M proteins, and we found a general perturbation of the host cell calcium (Ca2+) homeostasis and a selective rearrangement of the interorganelle contact sites. In vitro and in vivo biochemical analyses revealed that the binding of specific nanobodies to soluble regions of SARS-CoV-2 E protein reversed the observed phenotypes, suggesting that the E protein might be an important therapeutic candidate not only for vaccine development, but also for the clinical management of COVID designing drug regimens that, so far, are very limited.

DOI: https://doi.org/10.1038/s41419-023-05817-w