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PreprintCC BYbioRxiv

Caloric Restriction Promotes Ischemia/Reperfusion Cardioprotection Through Increased Mitochondrial Na+/Ca2+ Exchange

  • M. I. Queiroz
  • C. C. Caldeira da Silva
  • M. A. Cruz
  • J. D. Serna
  • L. R. Bechara
  • J. C. Ferreira
  • H. T. Facundo
  • A. J. Kowaltowski1
  1. 1Universidade de Sao Paulo
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Abstract

Caloric restriction (CR) protects against cardiac ischemia/reperfusion (I/R) injury, but the underlying mechanisms remain incompletely understood. Since mitochondrial Ca2+ overload and redox imbalance is a major driver of cardiac damage during reperfusion, we investigated if enhanced mitochondrial Ca2+ efflux contributes toward CR-induced cardioprotection. Rats were subjected to 16 weeks of ad libitum (AL) feeding or 40% caloric restriction. CR significantly increased mitochondrial Ca2+ retention capacity when Na+ ions were present, reduced H2O2 release, and increased the expression of proteins related to mitochondrial Ca2+ extrusion. In cardiomyocytes exposed to serum from CR rats, Ca2+ retention capacity also markedly increased, as well as Ca2+ efflux and the expression of extrusion proteins NCLX and TMEM65. Following I/R, CR hearts exhibited improved functional recovery accompanied by enhanced retention and increased mitochondrial Ca2+ efflux activity, as well as reduced H2O2 release compared to AL controls. Inhibition of mitochondrial Na+/Ca2+ exchange abolished the mitochondrial adaptive effects of CR, eliminating its protection against damage in cardiomyocytes and perfused hearts. These findings demonstrate that CR protects the heart from I/R injury by enhancing CGP-sensitive Na+-dependent mitochondrial Ca2+ efflux, preserving mitochondrial function, limiting redox imbalance, and improving post-ischemic cardiac recovery.

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Cite

BibTeXRIS
BibTeX
@misc{queiroz2026caloric,
  title = {{Caloric Restriction Promotes Ischemia/Reperfusion Cardioprotection Through Increased Mitochondrial Na+/Ca2+ Exchange}},
  author = {M. I. Queiroz and C. C. Caldeira da Silva and M. A. Cruz and J. D. Serna and L. R. Bechara and J. C. Ferreira and H. T. Facundo and A. J. Kowaltowski},
  howpublished = {bioRxiv},
  year = {2026},
  month = jul,
  doi = {10.64898/2026.07.20.739602},
  url = {https://www.biorxiv.org/content/10.64898/2026.07.20.739602v2},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Caloric Restriction Promotes Ischemia/Reperfusion Cardioprotection Through Increased Mitochondrial Na+/Ca2+ Exchange
AU  - M. I. Queiroz
AU  - C. C. Caldeira da Silva
AU  - M. A. Cruz
AU  - J. D. Serna
AU  - L. R. Bechara
AU  - J. C. Ferreira
AU  - H. T. Facundo
AU  - A. J. Kowaltowski
PY  - 2026
DA  - 2026/07/20
PB  - bioRxiv
DO  - 10.64898/2026.07.20.739602
UR  - https://www.biorxiv.org/content/10.64898/2026.07.20.739602v2
AB  - Caloric restriction (CR) protects against cardiac ischemia/reperfusion (I/R) injury, but the underlying mechanisms remain incompletely understood. Since mitochondrial Ca2+ overload and redox imbalance is a major driver of cardiac damage during reperfusion, we investigated if enhanced mitochondrial Ca2+ efflux contributes toward CR-induced cardioprotection. Rats were subjected to 16 weeks of ad libitum (AL) feeding or 40% caloric restriction. CR significantly increased mitochondrial Ca2+ retention capacity when Na+ ions were present, reduced H2O2 release, and increased the expression of proteins related to mitochondrial Ca2+ extrusion. In cardiomyocytes exposed to serum from CR rats, Ca2+ retention capacity also markedly increased, as well as Ca2+ efflux and the expression of extrusion proteins NCLX and TMEM65. Following I/R, CR hearts exhibited improved functional recovery accompanied by enhanced retention and increased mitochondrial Ca2+ efflux activity, as well as reduced H2O2 release compared to AL controls. Inhibition of mitochondrial Na+/Ca2+ exchange abolished the mitochondrial adaptive effects of CR, eliminating its protection against damage in cardiomyocytes and perfused hearts. These findings demonstrate that CR protects the heart from I/R injury by enhancing CGP-sensitive Na+-dependent mitochondrial Ca2+ efflux, preserving mitochondrial function, limiting redox imbalance, and improving post-ischemic cardiac recovery.
ER  -