VDACs are MOM's ruin: Mitochondrial DNA (mtDNA) is normally kept within the mitochondria. It can be released into the cytosol in response to stress and thus encounter cytosolic DNA sensors, triggering type I interferon responses. During apoptosis, mtDNA release is mediated by macropores in the mitochondrial outer membrane (MOM) created by oligomerization of the proteins BAX and BAK. Kim et al. found that during oxidative stress, mtDNA escapes instead through macropores formed by oligomerization of voltage-dependent anion channels (VDACs) (see the Perspective by Crow). In a mouse model of lupus, an inhibitor of VDAC oligomerization diminished mtDNA release and downstream signaling events. This treatment reduced lupus-like symptoms in the model, suggesting a potential therapeutic route for conditions mediated by mtDNA release. Science , this issue p. 1531 ; see also p. 1445

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.

Calcium ions (Ca2+) are crucial, ubiquitous, intracellular second messengers required for functional mitochondrial metabolism during uncontrolled proliferation of cancer cells. The mitochondria and the endoplasmic reticulum (ER) are connected via “mitochondria-associated ER membranes” (MAMs) where ER-mitochondria Ca2+ transfer occurs, impacting the mitochondrial biology related to several aspects of cellular survival, autophagy, metabolism, cell death sensitivity and metastasis, all cancer hallmarks. Cancer cells appear addicted to these constitutive ER-mitochondrial Ca2+ fluxes for their survival since they drive the TCA cycle and the production of mitochondrial substrates needed for nucleoside synthesis and proper cell cycle progression. In addition to this, the mitochondrial Ca2+ uniporter (MCU) and mitochondrial Ca2+ have been linked to hypoxia-inducible factor 1α (HIF1α signaling, enabling metastasis and invasion processes, but they can also contribute to cellular senescence induced by oncogenes and replication. Finally, proper ER-mitochondrial Ca2+ transfer seems to be a key event in the cell death response of cancer cells exposed to chemotherapeutics. In this review, we discuss the emerging role of ER-mitochondrial Ca2+ fluxes underlying these cancer-related features.