Mitochondrial Ca2+ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation.

Abstract

Severe hypoxia triggers apoptosis leads to myofibers loss and is attributable to impaired intracellular calcium (iCa2+ ) homeostasis, resulting in reduced muscle activity. Hypoxia increases intracellular Ca2+ by activating the release of Ca2+ from iCa2+ stores, however, the effect of increased [iCa2+ ] on the mitochondria of muscle cells at high-altitude hypoxia is largely unexplored. This study examined mitochondrial Ca2+ overload due to altered expression of mitochondrial calcium uptake 1 (MICU1), that is, a gatekeeper of the mitochondrial Ca2+ uniporter, impaired mitochondrial membrane potential (ΔΨm). p53 stabilization and its translocation to the mitochondria were observed following disrupted mitochondrial membrane integrity in myoblasts under hypoxia. Furthermore, the downstream effects of p53 led to the upregulation of proapoptotic proteins (Bax, Caspase-3, and cytochrome C) in myoblasts under hypoxia. Nanocurcumin-pyrroloquinoline quinone formulation (NCF; Indian patent no. 302877), developed to address hypoxia-induced consequences, was found to be beneficial in maintaining mitochondrial Ca2+ homeostasis and limiting p53 translocation into mitochondria under hypoxia in muscle myoblasts. NCF treatment also modulates heat shock proteins and apoptosis-regulating protein expression in myoblasts. Conclusively, we proposed that mitochondrial Ca2+ overload due to altered MICU1 expression intensifies apoptosis and mitochondrial dysfunctionality. The study also reported that NCF could improve mitochondrial [Ca2+ ] homeostasis and antiapoptotic ability in C2C12 myoblasts under hypoxia.

• Authors: Asha D Kushwaha, Namita Kalra, Rajeev Varshney, Deepika Saraswat
• Journal: IUBMB life (IUBMB Life) Vol. 75 Issue 8 Pg. 673-687 (08 2023) ISSN: 1521-6551 [Electronic] England
• PMID: 37002613 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 International Union of Biochemistry and Molecular Biology.

Chemical References

• Calcium
• Tumor Suppressor Protein p53
• Mitochondrial Membrane Transport Proteins

Topics

• Humans
• Calcium (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Proteostasis
• Mitochondria (metabolism)
• Myoblasts
• Apoptosis
• Hypoxia (metabolism)
• Mitochondrial Membrane Transport Proteins (metabolism)
• Membrane Potential, Mitochondrial