In several cancer cells, the specific localization of the glycolytic enzyme hexokinase-2 (HK2) at mitochondria-ER contact sites [called mitochondria-associated ER membranes (MAMs)] prevents mitochondrial Ca2+ overload, permeability transition pore (mPTP) opening and cell death by preventing ER Ca2+ release through IP3R (Ciscato et al., 2020; Figure 1A). The gene discussed is HK1; the disease is cancer.