Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling

Mitochondria are robust signaling organelle that regulate a variety of cellular functions. One of the key mechanisms that drive mitochondrial signaling is inter-organelle crosstalk. Mitochondria communicates with other organelles primarily via exchange of calcium (Ca²⁺), reactive oxygen species (ROS) and lipids across organelle membranes. Mitochondria has its own genome but a majority of mitochondrial proteins are encoded by nuclear genome. Therefore, several mitochondrial functions are controlled by nucleus via anterograde signaling. However, the role of mitochondria in driving expression of genes encoded by nuclear genome has recently gained attention. Recent studies from independent groups have demonstrated a critical role for mitochondrial Ca²⁺signaling in stimulating nuclear gene expression. These studies report that inhibition of mitochondrial Ca²⁺uptake through silencing of Mitochondrial Ca²⁺Uniporter (MCU) leads to Ca²⁺oscillations in the cytosol. The rise in cytosolic Ca²⁺ results in activation of Ca²⁺ sensitive transcription factors such as NFATs and NF-$\kappa$B. These transcription factors consequently induce expression of their target genes in the nuclear genome. It is important to highlight that these groups used different cell types and elegantly presented a phenomenon that is conserved across various systems. Notably, mitochondrial Ca²⁺ signaling mediated transcriptional regulation controls diverse cellular functions ranging from B-cell activation, melanogenesis and aging associated inflammation. Future studies on this signaling module would result in better understanding of this axis in human pathophysiology and could lead to development of novel therapeutic strategies.