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. Furthermore, the positively charged residues in the N-terminal domain of VDAC1 interact with mtDNA, promoting VDAC1 oligomerization. The VDAC oligomerization inhibitor VBIT-4 decreases mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. Thus, inhibiting VDAC oligomerization is a potential therapeutic approach for diseases associated with mtDNA release.

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. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics. Cellular organelles are no longer conceived as unconnected structures with isolated functions, but as dynamic and integrated compartments. The best-characterized membrane contact sites bridge the endoplasmic reticulum (ER) and mitochondria 1. The ER-the largest organelle in eukaryotic cells-controls protein folding, lipid synthesis and calcium storage. The folding capacity of the ER is constantly challenged by physiological demands and disease states. To sustain proteostasis, cells engage the unfolded protein response (UPR) 2 , a Carreras-Sureda et al.

Inter-organellar communication often takes the form of Ca2+ signals. These Ca2+ signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca2+ signals are the mitochondria. ER–mitochondrial Ca2+ transfer is possible through the existence of mitochondria-associated ER membranes (MAMs), ER structures that are in the proximity of the mitochondria. This creates a micro-domain in which the Ca2+ concentrations are manifold higher than in the cytosol, allowing for rapid mitochondrial Ca2+ uptake. In the mitochondria, the Ca2+ signal is decoded differentially depending on its spatiotemporal characteristics. While Ca2+ oscillations stimulate metabolism and constitute pro-survival signaling, mitochondrial Ca2+ overload results in apoptosis. Many chemotherapeutics depend on efficient ER–mitochondrial Ca2+ signaling to exert their function. However, several oncogenes and tumor suppressors present in the MAMs can alter Ca2+ signaling in cancer cells, rendering chemotherapeutics ineffective. In this review, we will discuss recent studies that connect ER–mitochondrial Ca2+ transfer, tumor suppressors and oncogenes at the MAMs, and chemotherapy.

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are highly specialized subcellular compartments that are shaped by ER subdomains juxtaposed to mitochondria but are biochemically distinct from pure ER and pure mitochondria. MAMs are enriched in enzymes involved in lipid synthesis and transport, channels for calcium transfer, and proteins with oncogenic/oncosuppressive functions that modulate cell signaling pathways involved in physiological and pathophysiological processes. The term “cancer” denotes a group of disorders that result from uncontrolled cell growth driven by a mixture of genetic and environmental components. Alterations in MAMs are thought to account for the onset as well as the progression and metastasis of cancer and have been a focus of investigation in recent years. In this review, we present the current state of the art regarding MAM-resident proteins and their relevance, alterations, and deregulating functions in different types of cancer from a cell biology and clinical perspective.

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