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.

ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.

Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca handling compromises mitochondrial function and affects neuronal health.

Loss of INPP5K attenuates IP-induced Ca responses in the glioblastoma cell line U-251 MG cells.

INPP5K (inositol polyphosphate 5-phosphatase K) is an endoplasmic reticulum (ER)-resident enzyme that acts as a phosphoinositide (PI) 5-phosphatase, capable of dephosphorylating various PIs including PI 4,5-bisphosphate (PI(4,5)P), a key phosphoinositide found in the plasma membrane. Given its ER localization and substrate specificity, INPP5K may play a role in ER-plasma membrane contact sites. Furthermore, PI(4,5)P serves as a substrate for phospholipase C, an enzyme activated downstream of extracellular agonists acting on Gq-coupled receptors or tyrosine-kinase receptors, leading to IP production and subsequent release of Ca from the ER, the primary intracellular Ca storage organelle.

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).

Dysregulated Ca Homeostasis as a Central Theme in Neurodegeneration: Lessons from Alzheimer's Disease and Wolfram Syndrome.

Calcium ions (Ca) operate as important messengers in the cell, indispensable for signaling the underlying numerous cellular processes in all of the cell types in the human body. In neurons, Ca signaling is crucial for regulating synaptic transmission and for the processes of learning and memory formation. Hence, the dysregulation of intracellular Ca homeostasis results in a broad range of disorders, including cancer and neurodegeneration.

Uniting the divergent Wolfram syndrome-linked proteins WFS1 and CISD2 as modulators of Ca signaling.

Mutations in (which encodes Wolframin, WFS1) and (which encodes CDGSH iron sulfur domain 2) result in Wolfram syndrome (WS), a rare genetic disorder that starts with juvenile diabetes and progresses to neurological dysfunction. WFS1 and CISD2 belong to different protein families with distinct properties. Despite differences between WFS1 and CISD2, loss-of-function mutations in these proteins result in similar disease phenotypes, suggesting that they have convergent roles.

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.