Cell packing comes under the lens

How ER stress gives cells the CHOP L i et al. explain how prolonged stress sparks the endoplasmic reticulum (ER) to release its calcium stores, inducing cells to undergo apoptosis in several aging-related diseases. Stressful conditions cause misfolded proteins to accumulate in the ER. Cells try to recover by slowing down translation and increasing production of their protein folding machinery. But if the stress continues, prolonged expression of a transcription factor called CHOP promotes cell death instead. The apoptotic machinery is triggered by calcium released from the ER, but how CHOP induces this step wasn't known. Li et al. zoomed in on two ER proteins—an oxidase called ERO1-␣ and the calcium channel IP3R—to connect the dots between CHOP induction and calcium release. ERO1-␣ is a transcriptional target of CHOP, and its reexpression in cells lacking CHOP restored the cell death pathway. On the other hand, knocking down ERO1-␣ or IP3R prevented calcium release and apoptosis in response to ER stress. Insulin-resistant obese mice—known to suffer increased ER stress—showed elevated IP3R-dependent calcium release, indicating that the pathway operates in vivo. The researchers think that ERO1-␣ oxidizes the ER lumen, promoting the formation of a key disulphide bond in IP3R that makes the channel more active. Senior author Ira Tabas points out the importance of understanding this mechanism further: mice lacking CHOP are protected against cell death arising from a variety of pathologies, including advanced atherosclerosis, diabetes, and neurodegeneration. The long and shor t of mitochondrial fusion T wo isoforms of a yeast GTPase combine— with the help of a special phospholipid—to drive mitochondrial inner membrane fusion, DeVay et al. report. Mitochondria constantly merge and divide to distribute their activity appropriately throughout the cell. When coming together, these organelles use proteins related to the endocytic GTPase dynamin to fuse both their outer and inner membranes. In yeast, two different isoforms of a GTPase called Mgm1 drive inner membrane fusion: a short soluble form (s-Mgm1) that is proteolytically cleaved from a longer, transmembrane version (l-Mgm1). Both isoforms are required for fusion, but their precise contributions to the process were unclear. DeVay et al. expressed the proteins and examined their association with liposomes mimicking either the mitochondrial inner or outer membranes. Both s-Mgm1 and l-Mgm1 preferred inner membrane liposomes—the key determinant was an inner membrane phospholipid called cardiolipin. Moreover, although s-Mgm1 on its own was monomeric and inactive, cardiolipin stimulated the protein's GTPase activity …