Severe burn-induced mitochondrial recruitment of calpain causes aberrant mitochondrial dynamics and heart dysfunction

Abstract

Mitochondrial damage is an important cause of heart dysfunction after severe burn injury. However, the pathophysiological process remains unclear. This study aims to examine the mitochondrial dynamics in the heart and the role of μ-calpain, a cysteine protease, in this scenario. Rats were subjected to severe burn injury treatment, and the calpain inhibitor MDL28170 was administered intravenously 1 h before or after burn injury. Rats in the burn group displayed weakened heart performance and decreased mean arterial pressure, which was accompanied by a diminishment of mitochondrial function. The animals also exhibited higher levels of calpain in mitochondria, as reflected by immunofluorescence staining and activity tests. In contrast, treatment with MDL28170 before any severe burn diminished these responses to a severe burn. Burn injury decreased the abundance of mitochondria and resulted in a lower percentage of small mitochondria and a higher percentage of large mitochondria. Furthermore, burn injury caused an increase in the fission protein DRP1 in the mitochondria and a decrease in the inner membrane fusion protein OPA1. Similarly, these alterations were also blocked by MDL28170. Of note, inhibition of calpain yielded the emergence of more elongated mitochondria along with membrane invagination in the middle of the longitude, which is an indicator of the fission process. Finally, MDL28170, administered 1 h after burn injury, preserved mitochondrial function and heart performance, and increased the survival rate. Overall, these results provided the first evidence that mitochondrial recruitment of calpain confers heart dysfunction after severe burn injury, which involves aberrant mitochondrial dynamics.

Nuclear accumulated μ-calpain in AT2 cell participates in pulmonary fibrosis via inactivating FoxO3a

“…Furthermore, these results corroborate the point that modi cation of transcription factor activity is an important step to trigger mesenchymal transition. However, the results are in contrast to our previous ndings showing an accumulation of µ-calpain in the plasma membrane and mitochondria after stressful stimulation [14,15]. Thus, the unidenti ed regulator, which is in charge of the trajectory of µcalpain, warrants to be elucidated.…”

“…µ-calpain is a superfamily of Ca 2+ -dependent nonlysosomal cysteine protease, which consist of a large catalytic subunit, namely calpain 1 (CAPN1) and a small regulatory subunit CAPN4 [13]. We and others have demonstrated that CAPNs participate in a variety of pathophysiological processes, i.e., plasma membrane disruption, mitochondrial damage, transform of vascular permeability and cell motility [14][15][16][17]. Of note, µ-calpain is implicated in the progression of IPF patients [18,19].…”

Altered Profiles of Extracellular Mitochondrial Dna in Immunoparalyzed Pediatric Patients After Thermal Injury

“…This susceptibility to mutations results in significant heteroplasmy of mitochondria. Although mitochondrial damage, metabolic dysfunction, and ROS burden have been described in multiple tissues after thermal injury in animal models (15–20), we do not know how it relates to mtDNA mutation burden and immune function after thermal injury in pediatric patients. Accordingly, we sought to determine whether changes in extracellular mtDNA content and mutation load are associated with changes in inflammatory response and innate and adaptive immune function in a cohort of pediatric patients after thermal injury.…”