Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder.

DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case-series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated.

CISD2 counteracts the inhibition of ER-mitochondrial calcium transfer by anti-apoptotic BCL-2.

CISD2, a 2Fe2S cluster domain-containing protein, is implicated in Wolfram syndrome type 2, longevity and cancer. CISD2 is part of a ternary complex with IP receptors (IPRs) and anti-apoptotic BCL-2 proteins and enhances BCL-2's anti-autophagic function. Here, we examined how CISD2 impacted the function of BCL-2 in apoptosis and in controlling IPR-mediated Ca signaling.

Intracellular BAPTA directly inhibits PFKFB3, thereby impeding mTORC1-driven Mcl-1 translation and killing MCL-1-addicted cancer cells.

Intracellular Ca signals control several physiological and pathophysiological processes. The main tool to chelate intracellular Ca is intracellular BAPTA (BAPTA), usually introduced into cells as a membrane-permeant acetoxymethyl ester (BAPTA-AM). Previously, we demonstrated that BAPTA enhanced apoptosis induced by venetoclax, a BCL-2 antagonist, in diffuse large B-cell lymphoma (DLBCL).

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

Endoplasmic reticulum (ER)-mitochondria contact sites are crucial to allow Ca flux between them and a plethora of proteins participate in tethering both organelles together. Inositol 1,4,5-trisphosphate receptors (IPRs) play a pivotal role at such contact sites, participating in both ER-mitochondria tethering and as Ca-transport system that delivers Ca from the ER towards mitochondria. At the ER-mitochondria contact sites, the IPRs 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).

The alkalinizing, lysosomotropic agent ML-9 induces a pH-dependent depletion of ER Ca stores in cellulo.

ML-9 elicits a broad spectrum of effects in cells, including inhibition of myosin light chain kinase, inhibition of store-operated Ca entry and lysosomotropic actions that result in prostate cancer cell death. Moreover, the compound also affects endoplasmic reticulum (ER) Ca homeostasis, although the underlying mechanisms remain unclear. We found that ML-9 provokes a rapid mobilization of Ca from ER independently of IPRs or TMBIM6/Bax Inhibitor-1, two ER Ca-leak channels.

A non-canonical role for pyruvate kinase M2 as a functional modulator of Ca signalling through IP receptors.

Pyruvate kinase isoform M2 (PKM2) is a rate-limiting glycolytic enzyme that is widely expressed in embryonic tissues. The expression of PKM2 declines in some tissues following embryogenesis, while other pyruvate kinase isozymes are upregulated. However, PKM2 is highly expressed in cancer cells and is believed to play a role in supporting anabolic processes during tumour formation.

Dynamic control of mitochondria-associated membranes by kinases and phosphatases in health and disease.

Membrane-contact sites are getting more and more credit for their indispensable role in maintenance of cell function and homeostasis. In the last decades, the ER-mitochondrial contact sites in particular received a lot of attention. While our knowledge of ER-mitochondrial contact sites increases steadily, the focus often lies on a static exploration of their functions.

Balancing ER-Mitochondrial Ca Fluxes in Health and Disease.

Organelles cooperate with each other to control cellular homeostasis and cell functions by forming close connections through membrane contact sites. Important contacts are present between the endoplasmic reticulum (ER), the main intracellular Ca-storage organelle, and the mitochondria, the organelle responsible not only for the majority of cellular ATP production but also for switching on cell death processes. Several Ca-transport systems focalize at these contact sites, thereby enabling the efficient transmission of Ca signals from the ER toward mitochondria.

Cancer cell death strategies by targeting Bcl-2's BH4 domain.

The Bcl-2-family proteins have long been known for their role as key regulators of apoptosis. Overexpression of various members of the family is associated with oncogenesis. Its founding member, anti-apoptotic Bcl-2 regulates cell death at different levels, whereby Bcl-2 emerged as a major drug target to eradicate cancers through cell death.

BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca-dependent mPTP opening.

Anti-apoptotic Bcl-2 critically controls cell death by neutralizing pro-apoptotic Bcl-2-family members at the mitochondria. Bcl-2 proteins also act at the endoplasmic reticulum, the main intracellular Ca-storage organelle, where they inhibit IP receptors (IPR) and prevent pro-apoptotic Ca-signaling events. IPR channels are targeted by the BH4 domain of Bcl-2.

DLBCL Cells with Acquired Resistance to Venetoclax Are Not Sensitized to BIRD-2 But Can Be Resensitized to Venetoclax through Bcl-XL Inhibition.

Anti-apoptotic Bcl-2-family members are frequently dysregulated in both blood and solid cancers, contributing to their survival despite ongoing oncogenic stress. Yet, such cancer cells often are highly dependent on Bcl-2 for their survival, a feature that is exploited by so-called BH3-mimetic drugs. Venetoclax (ABT-199) is a selective BH3-mimetic Bcl-2 antagonist that is currently used in the clinic for treatment of chronic lymphocytic leukemia patients.

Cytosolic Ca oversees the MASs production of pyruvate for the mitochondrial market.

It is generally accepted that mitochondrial Ca controls the pace of mitochondrial bioenergetics and thus ATP production. Szibor et al. challenge this paradigm, proposing that the balance between ATP consumption and production depends on mitochondrial pyruvate supply via the malate-aspartate shuttle (MAS) and is controlled by cytosolic Ca.

VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease.

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type Ι interferon (IFN) response. Mitochondrial outer membrane permeabilization, which is required for mtDNA release, has been extensively studied in apoptotic cells, but little is known about its role in live cells. We found that oxidatively stressed mitochondria release short mtDNA fragments via pores formed by the voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane.

Publisher Correction: Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics.

Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions.

Therapeutic implications of novel peptides targeting ER-mitochondria Ca-flux systems.

Intracellular Ca-flux systems located at the ER-mitochondrial axis govern mitochondrial Ca balance and cell fate. Multiple yet incurable pathologies are characterized by insufficient or excessive Ca fluxes toward the mitochondria, in turn leading to aberrant cell life or death dynamics. The discovery and ongoing molecular characterization of the main interorganellar Ca gateways have resulted in a novel class of peptide tools able to regulate relevant protein-protein interactions (PPIs) underlying this signaling scenario.

ABT-199 (Venetoclax), a BH3-mimetic Bcl-2 inhibitor, does not cause Ca -signalling dysregulation or toxicity in pancreatic acinar cells.

Background And Purpose: Many cancer cells depend on anti-apoptotic B-cell lymphoma 2 (Bcl-2) proteins for their survival. Bcl-2 antagonism through Bcl-2 homology 3 (BH3) mimetics has emerged as a novel anti-cancer therapy. ABT-199 (Venetoclax), a recently developed BH3 mimetic that selectively inhibits Bcl-2, was introduced into the clinic for treatment of relapsed chronic lymphocytic leukaemia.

Emerging molecular mechanisms in chemotherapy: Ca signaling at the mitochondria-associated endoplasmic reticulum membranes.

Inter-organellar communication often takes the form of Ca signals. These Ca signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca signals are the mitochondria.

Alterations in Ca Signalling via ER-Mitochondria Contact Site Remodelling in Cancer.

Inter-organellar contact sites establish microdomains for localised Ca-signalling events. One of these microdomains is established between the ER and the mitochondria. Importantly, the so-called mitochondria-associated ER membranes (MAMs) contain, besides structural proteins and proteins involved in lipid exchange, several Ca-transport systems, mediating efficient Ca transfer from the ER to the mitochondria.