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Commentary on ‘ER-mitochondria tethering by PDZD8 regulates Ca dynamics in mammalian neurons’ by Hirabayashi et al., Science 2017. In cardiomyocytes, large amounts of calcium (Ca2þ) are released from the sarcoplasmic reticulum (SR) into the cytosol with each heartbeat. This Ca2þ is directed to sarcomeric structures to initiate muscle contraction. Within the myocytes, Ca2þ is also crucial for various signalling pathways, as it regulates cell metabolism, cell death, and nuclear gene transcription. In an attempt to understand how Ca2þ controls different cellular functions when the heart is continuously subjected to large periodic Ca2þ signals that flood through the cytoplasm and nucleus during each contraction, the concept of subcellular microdomains as highly specialized signalling hubs has emerged. In those spatially restricted spaces, numerous factors including Ca2þ levels, oxygen/glucose availability and kinase/phosphatase activity can be locally altered, yet determining overall cardiomyocyte vulnerability to diverse functional and structural outcomes (i.e. contractile function, remodelling, and apoptosis). One such example that drew significant attention in the recent years is the subcellular space between the mitochondria and the SR. Specific areas in which the distance between the organelle membranes is <30 nm have been described, and the occurrence of such intimate inter-membrane networks was termed ‘tethering’. Tethering has been shown to play multiple roles in cardiomyocytes, thereof the Ca2þ cross-talk is arguably the most important. Advancement of powerful imaging techniques facilitated mapping of the tethering proteins responsible for the three-dimensional association of mitochondrial and SR membranes in mouse ventricular myocardium; yet the molecular identity of the proteins controlling this inter-organelle apposition is still debated. For its enrichment at SR-mitochondrial junctions, Mitofusin2 was suggested to play a critical role in preserving the inter-organelle tethering and Ca2þ transfer. On the other hand, a meticulous study by Filadi et al. showed that Mitofusin2 deletion actually increases endoplasmic reticulum (ER)-mitochondria coupling in mouse embryonic fibroblasts in which Mitofusin2 is ablated or transiently silenced, bringing a level of uncertainty to its exact role in securing the tight organelle contacts. The only ER-mitochondrial tethering complex with known molecular composition is the yeast ER-mitochondria encounter structure (ERMES). It consists of at least four proteins: the ER-membrane–residing protein maintenance of mitochondrial morphology protein 1 (Mmm1), the cytosolic linker mitochondrial distribution and morphology protein 12 (Mdm12), and the integral outer mitochondrial membrane proteins Mdm34 and Mdm10. From a functional perspective, a specific ERMES ortholog would be largely expected in eukaryotic cells. Hirabayashi et al. recently demonstrated that PDZ domain containing protein 8 (PDZD8) is located at the interface of ER and mitochondrial membranes and serves to zipper them together, as well as that it is essential for Ca2þ transfer from ER to mitochondria in mammalian neurons. Initial Protein Data Bank search and computer modelling Dr Senka Ljubojevic-Holzer earned a PhD in Molecular Medicine at the Medical University of Graz (Austria). After graduation, she was granted a ‘Hertha Firnberg’ fellowship for exceptional young female scientists (2013–-2017) from the Austrian Science Fund. The project investigating subcellular ion homeostasis and excitation-transcription coupling was allocated at the University of California Davis (USA) and the Medical University of Graz (Austria). Dr Ljubojevic-Holzer will continue her research in the field of myocardial remodelling in hypertrophy and heart failure within the frame of senior post-doctoral fellowship ‘Elise Richter’, which she was granted last year (2017-–2020).

The Secret of the Kissing Cousins: an ER-mitochondrial tethering protein regulates Ca2+ crosstalk in mammalian neurons