PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control

Abstract

Background Dendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been characterized as a guide for impaired mitochondria that can keep mitochondrial homeostasis. However, its role in the function of DCs during sepsis and the related mechanisms remain obscure. In our study, we elucidated the effect of PINK1 on DC function during sepsis and its underlying mechanism of action. Methods Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) treatment were used as in vivo and in vitro sepsis models, respectively. Results We found that changes in mitochondrial PINK1 expression of DCs paralleled changes in DC function during sepsis. The ratio of DCs expressing MHC-II, CD86, and CD80, the mRNAs level of dendritic cells expressing TNF-α and IL-12, and the level of DC-mediated T-cell proliferation were all decreased, both in vivo and in vitro during sepsis, when PINK1 was knocked out. This suggested that PINK1 knockout prevented the function of DCs during sepsis. Furthermore, PINK1 knockout inhibited Parkin RBR E3 ubiquitin protein (Parkin)-dependent mitophagy and enhanced dynamin-related protein 1 (Drp1)-related mitochondrial fission, and the negative effects of PINK1 knockout on DC function following LPS treatment were reversed by Parkin activation and Drp1 inhibitor. Knockout of PINK1 also increased apoptosis of DCs and the mortality of CLP mice. Conclusion Our results indicated that PINK1 protected against DC dysfunction during sepsis through the regulation of mitochondrial quality control.

Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death

“…Thirdly, organelle-specific autophagy, which is a significant subtype of autophagy, specifically aims to degrade various organelles in order to maintain their quality. In sepsis, the dysfunction of DCs was prevented by regulating the quality control of mitochondria through protein tyrosine phosphatase (PTEN)induced putative kinase 1 (PINK1)-mediated mitophagy, as indicated by a report [58].…”

Mechanism and role of mitophagy in the development of severe infection

“…Mitophagy survives effector CD4 + T cells by inhibiting the production of mTOR pathway-dependent mROS [ 90 ]. The role of dendritic cells (DCs) is also impaired in sepsis and the state of DCs positively correlated with the level of PINK1-dependent mitophagy [ 115 , 116 ]. The B cells in the germinal center exhibit a highest mitophagy rate [ 117 ].…”

Restoring the infected powerhouse: Mitochondrial quality control in sepsis

“…By this process, a reduction in PINK1 inhibits mitophagy, inadvertently elevating mitochondrial fragmentation through dynamin-related protein 1 (Drp1)-related mitochondrial fission, which, however, can be counteracted by parkin overexpression. Hence, PINK1 primarily ensures protection by bolstering mitophagy and curbing mitochondrial fragmentation [ 132 ].…”