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Publication : ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca<sup>2+</sup> Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ.

First Author  Pavez-Giani MG Year  2021
Journal  Int J Mol Sci Volume  22
Issue  9 PubMed ID  33922643
Mgi Jnum  J:308924 Mgi Id  MGI:6751194
Doi  10.3390/ijms22094427 Citation  Pavez-Giani MG, et al. (2021) ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIdelta. Int J Mol Sci 22(9)
abstractText  ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca(2+) handling, which resulted in sarcoplasmic reticulum Ca(2+) overloading. The effects of IF1 on Ca(2+) handling were associated with the cytosolic activation of calcium-calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKIIdeltaC was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca(2+) handling and mitochondrial-to-nuclear crosstalk involving CaMKII.
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