TY - JOUR
T1 - Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis
AU - Zhang, Xianghong
AU - Yuan, Du
AU - Sun, Qian
AU - Xu, Li
AU - Lee, Emma
AU - Lewis, Anthony J.
AU - Zuckerbraun, Brian S.
AU - Rosengart, Matthew R.
N1 - Funding Information:
All animal experiments were performed in accordance with the U.S. National Institutes of Health guidelines under protocols approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh. We randomly grouped 8-to 12-wk-old male C57BL/6J mice and assigned them to a specific experiment. Investigators who treated animals knew the treatment groups and collected samples, which were then analyzed by other investigators who were blinded to the specific treatment.
Funding Information:
The authors thank Kevin P. Mollen and John E. Griepentrog (both from the University of Pittsburgh) for their assistance in interpreting the final collective data and reviewing the final manuscript. This work was supported by the U.S. National Institutes of Health, National Institute of General Medical Sciences Grant R01-GM082852 (to M.R.R.), and the Surgical Infection Society Junior Faculty Fellowship Award (to X.Z.). The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2017/10
Y1 - 2017/10
N2 - During sepsis and shock states, mitochondrial dysfunction occurs. Consequently, adaptive mechanisms, such as fission, fusion, and mitophagy, are induced to eliminate damaged portions or entire dysfunctional mitochondria. The regulatory PINK1/Parkin and DJ-1 pathways are strongly induced by mitochondrial depolarization, although a direct link between loss of mitochondrial membrane potential (ΔΨ) and mitophagy has not been identified. Mitochondria also buffer Ca2+, and their buffering capacity is dependent on ΔΨ. Here, we characterize a role for calcium/calmodulin-dependent protein kinase (CaMK) I in the regulation of these mechanisms. Loss of ΔΨ with either pharmacologic depolarization or LPS leads to Ca2+-dependent mitochondrial recruitment and activation of CaMKI that precedes the colocalization of PINK1/Parkin and DJ-1. CaMKI is required and serves as both a PINK1 and Parkin kinase. The mechanisms operate in both immune and nonimmune cells and are induced in in vivo models of endotoxemia, sepsis, and hemorrhagic shock. These data support the idea that CaMKI links mitochondrial stress with the PINK1/Parkin and DJ-1 mechanisms of mitophagy.
AB - During sepsis and shock states, mitochondrial dysfunction occurs. Consequently, adaptive mechanisms, such as fission, fusion, and mitophagy, are induced to eliminate damaged portions or entire dysfunctional mitochondria. The regulatory PINK1/Parkin and DJ-1 pathways are strongly induced by mitochondrial depolarization, although a direct link between loss of mitochondrial membrane potential (ΔΨ) and mitophagy has not been identified. Mitochondria also buffer Ca2+, and their buffering capacity is dependent on ΔΨ. Here, we characterize a role for calcium/calmodulin-dependent protein kinase (CaMK) I in the regulation of these mechanisms. Loss of ΔΨ with either pharmacologic depolarization or LPS leads to Ca2+-dependent mitochondrial recruitment and activation of CaMKI that precedes the colocalization of PINK1/Parkin and DJ-1. CaMKI is required and serves as both a PINK1 and Parkin kinase. The mechanisms operate in both immune and nonimmune cells and are induced in in vivo models of endotoxemia, sepsis, and hemorrhagic shock. These data support the idea that CaMKI links mitochondrial stress with the PINK1/Parkin and DJ-1 mechanisms of mitophagy.
KW - Autophagy
KW - Macrophage
KW - Mitochondria
KW - Mitochondrial membrane potential
UR - http://www.scopus.com/inward/record.url?scp=85030628096&partnerID=8YFLogxK
U2 - 10.1096/fj.201601096RRR
DO - 10.1096/fj.201601096RRR
M3 - Article
C2 - 28615325
AN - SCOPUS:85030628096
SN - 0892-6638
VL - 31
SP - 4382
EP - 4395
JO - FASEB Journal
JF - FASEB Journal
IS - 10
ER -