Mitochondrial calcium: Transport and modulation of cellular processes in homeostasis and cancer (Review).

In addition to their role in providing cellular energy, mitochondria fulfill a key function in cellular calcium management. The present review provides an integrative view of cellular and mitochondrial calcium homeostasis, and discusses how calcium regulates mitochondrial dynamics and functionality, thus affecting various cellular processes. Calcium crosstalk exists in the domain created between the endoplasmic reticulum and mitochondria, which is known as the mitochondria‑associated membrane (MAM), and controls cellular homeostasis. Calcium signaling participates in numerous biochemical and cellular processes, where calcium concentration, temporality and durability are part of a regulated, finely tuned interplay in non‑transformed cells. In addition, cancer cells modify their MAMs, which consequently affects calcium homeostasis to support mesenchymal transformation, migration, invasiveness, metastasis and autophagy. Alterations in calcium homeostasis may also support resistance to apoptosis, which is a serious problem facing current chemotherapeutic treatments. Notably, mitochondrial dynamics are also affected by mitochondrial calcium concentration to promote cancer survival responses. Dysregulated levels of mitochondrial calcium, alongside other signals, promote mitoflash generation in tumor cells, and an increased frequency of mitoflashes may induce epithelial‑to‑mesenchymal transition. Therefore, cancer cells remodel their calcium balance through numerous mechanisms that support their survival and growth.