Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis

SIMPLE SUMMARY: Several important cellular functions are finely tuned by the physical and functional interactions between mitochondria and other organelles, such as lipid trafficking, mitochondrial dynamics, calcium flow and Endoplasmic Reticulum stress. These functions in turn impact on apoptosis, autophagy, cell proliferation and differentiation, playing an important role in the pathogenesis of various human diseases. Mitochondria are closely interconnected with several organelles, such as Endoplasmic Reticulum, lipid droplets, Golgi apparatus, lysosomes, melanosomes and peroxisomes, through physical contacts. Several findings demonstrated that these interaction sites are important to fulfill specific cellular functions. In this review, we will highlight the role of membrane contact sites with mitochondria in modulating mitochondrial metabolism and intracellular signaling in the context of cancer development and progression, with a special focus on calcium signaling. In particular, we will discuss on mitochondria–ER, mitochondria–lysosomes and mitochondria–peroxisomes contact sites. ABSTRACT: Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling.