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. 2021 Sep 30;22(19):10579. doi: 10.3390/ijms221910579

Figure 4.

Figure 4

Schematic drawing showing metabolic remodeling, calcium cycling dysregulation and altered signaling in heart failure. Green arrows: promote signaling or activity. Turquoise arrows, rectangle or circle denotes decrease in signaling, activity or expression. Red rectangle or circle denotes increase in activity or expression. The deeper the intensity of the turquoise or red color, the higher is the degree in downregulation or upregulation, respectively, of protein activity or expression. Red up and down arrows indicate an increase in BNIP3 expression and a decrease in MCU expression, respectively. FA metabolism and mt-FA-β-oxidation, glycolysis, TCA and OXPHOS are attenuated in HF. SIRT3 expression is decreased in HF leading to mt-protein hyperacetylation. Enhanced MAPK (JNK) signaling inhibits Bcl-2 and MFN2 leading to ER-mt calcium dysregulation, mt-fission and apoptosis. Perturbations in calcium cycling and ER-mt tethering are evident in HF. ER calcium is depleted due to an enhanced ER calcium leak via RYR2, and a decrease in ER calcium uptake via SERCA2a leading to an increase in cytosolic calcium. Overall PKA signaling is attenuated in HF. Most importantly, decrease in PKA signaling and enhanced calcineurin activity at the ER-mt interface leads to (1) enhanced mt-fission, through recruitment of DRP1 to the mt-outer membrane; (2) decrease in ETC activity and OXPHOS; and (3) decreased in p-S16-PLN leading to further impairment in SERCA2a activity. Increases in IP3 abundance and BNIP3 expression lead to enhanced calcium release via the IP3R and enhanced calcium uptake via the VDAC1 channels, respectively. This is due to conformational change (oligomerization) of VDAC1. Enhanced CaMKIIδ expression or activity enhances mt-calcium uptake via MCU complex leading to mt-matrix calcium overload and mt-dysfunction. Mitochondrial calcium efflux is likely to be affected as well. It is unclear whether there is post-translational modification (??) and decrease in activity or expression of LETM1 and AKAP1 in HF. Abbreviations are listed under Figure 2.