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. Author manuscript; available in PMC: 2021 Jul 17.
Published in final edited form as: Circ Res. 2020 Jul 16;127(3):427–447. doi: 10.1161/CIRCRESAHA.120.316958

Figure 3. Mitochondrial mechanisms of myofibroblast differentiation and persistence.

Figure 3.

(A) Pro-fibrotic stressors increase ROS production in the mitochondria, which then results in an increased and sustained intracellular ROS load, in part, through the downregulation of SOD2 and catalase. Increases in intracellular ROS in turn activates p38 and ERK1/2 signaling pathways, which are known to increase the transcription of the fibrotic gene program. (B) A key feature of myofibroblasts is their resistance to apoptosis. Mitochondrial cytochrome c (Cyto c) release is prevented through the upregulation of anti-apoptotic factors (BLC-2, BCL-XL) while pro-apoptotic factors (BAX, BAK) are downregulated. Reduced activation of the proteolytic caspase cascade due to decreased cytochrome c release from the mitochondria contributes to the persistence of myofibroblasts in the injured heart by imparting a resistance to cell death. TGFβ – transforming growth factor beta; AngII – angiotensin II; ROS – reactive oxygen species; SOD2 - superoxide dismutase 2; MKPs – mitogen-activated protein kinases; BCL-2 – B-cell lymphoma 2; BCL-XL - B-cell lymphoma-extra large; BAX – Bcl-2-associated X protein; BAK – Bcl-2 homologous antagonist killer; Casp9/3 – caspase 9/3.