Figure 2. Mechanistic actions of Ca²⁺ during myofibroblast differentiation.

Mechanical activation of TRP channels permits Ca²⁺ entry from the extracellular space, increasing cytosolic [Ca²+]. Additionally, activation of the G_q/PLC/IP₃ pathway allows for IP₃-mediated Ca²⁺ release from the ER, further increasing cytosolic [Ca²+]. This increase in cytosolic [Ca²+] activates calmodulin-dependent calcineurin phosphatase (CaM/CN) to dephosphorylate and permit nuclear translocation of NFAT and subsequent activation of the fibrotic gene program. While mitochondria can act to buffer increases in cytosolic [Ca²+] through the mitochondrial calcium uniporter complex (mtCU), the transcriptional upregulation of MICU1 alters mtCU gating, reducing _mCa²⁺ uptake and reducing _m[Ca²⁺]. As _m[Ca²⁺] is an activator of numerous dehydrogenases and phosphatases within the mitochondria, this significantly reduces pyruvate oxidation and overall Krebs cycle flux. TGFβ – transforming growth factor beta; AngII – angiotensin II; ET-1 – endothelin 1; TGFBR1/2 – TGFβ receptor 1/2; TRPs – transient receptor potential channels; PLC – protein lipase C; PIP₂ – phosphatidylinositol 4,5-bisphosphate; DAG – diacylglycerol; Pyr – pyruvate; PDH – pyruvate dehydrogenase; PDP – pyruvate dehydrogenase phosphatase; MICU1 – mitochondrial calcium uptake 1; NFAT – nuclear factor of activated T-cells; IDH – isocitrate dehydrogenase; ⍺KGDH - ⍺-ketoglutarate dehydrogenase; Col1a1 – collagen 1 type 1; Fn – fibronectin.