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Article

Critical Roles of Calpastatin in Ischemia/Reperfusion Injury in Aged Livers

1
Department of Surgery, University of Florida, Gainesville, FL 32610, USA
2
Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA
3
Department of Aging and Geriatric Research, University of Florida, Gainesville, FL 32610, USA
4
Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO 63110, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Wen-Xing Ding
Cells 2021, 10(8), 1863; https://doi.org/10.3390/cells10081863
Received: 16 June 2021 / Revised: 16 July 2021 / Accepted: 18 July 2021 / Published: 23 July 2021
(This article belongs to the Special Issue Autophagy Meets Aging)
Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. Adenoviral vector was used to overexpress CAST. Significant cell death was observed only in reperfused aged hepatocytes. Before the commencement of ischemia, CAST expression in aged human and mouse livers and mouse hepatocytes was markedly greater than that in young counterparts. However, reperfusion substantially decreased CAST in aged human and mouse livers. In hepatocytes, reperfusion rapidly depleted aged cells of CAST, cleaved autophagy-related protein 5 (ATG5), and induced defective autophagy and MPT onset, all of which were blocked by CAST overexpression. Furthermore, mitochondrial morphology was shifted toward an elongated shape with CAST overexpression. In conclusion, CAST in aged livers is intrinsically short-lived and lost after short I/R. CAST depletion contributes to age-dependent liver injury after I/R. View Full-Text
Keywords: liver; ischemia/reperfusion; autophagy; mitochondria; calpastatin liver; ischemia/reperfusion; autophagy; mitochondria; calpastatin
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MDPI and ACS Style

Flores-Toro, J.; Chun, S.-K.; Shin, J.-K.; Campbell, J.; Lichtenberger, M.; Chapman, W.; Zendejas, I.; Behrns, K.; Leeuwenburgh, C.; Kim, J.-S. Critical Roles of Calpastatin in Ischemia/Reperfusion Injury in Aged Livers. Cells 2021, 10, 1863. https://doi.org/10.3390/cells10081863

AMA Style

Flores-Toro J, Chun S-K, Shin J-K, Campbell J, Lichtenberger M, Chapman W, Zendejas I, Behrns K, Leeuwenburgh C, Kim J-S. Critical Roles of Calpastatin in Ischemia/Reperfusion Injury in Aged Livers. Cells. 2021; 10(8):1863. https://doi.org/10.3390/cells10081863

Chicago/Turabian Style

Flores-Toro, Joseph, Sung-Kook Chun, Jun-Kyu Shin, Joan Campbell, Melissa Lichtenberger, William Chapman, Ivan Zendejas, Kevin Behrns, Christiaan Leeuwenburgh, and Jae-Sung Kim. 2021. "Critical Roles of Calpastatin in Ischemia/Reperfusion Injury in Aged Livers" Cells 10, no. 8: 1863. https://doi.org/10.3390/cells10081863

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