TY - JOUR
T1 - Prominent Mitochondrial Injury as an Early Event in Heme Protein-Induced Acute Kidney Injury
AU - Singh, Raman Deep
AU - Croatt, Anthony J.
AU - Ackerman, Allan W.
AU - Grande, Joseph P.
AU - Trushina, Eugenia
AU - Salisbury, Jeffrey L.
AU - Christensen, Trace A.
AU - Adams, Christopher M.
AU - Tchkonia, Tamara
AU - Kirkland, James L.
AU - Nath, Karl A.
N1 - Publisher Copyright:
Copyright © 2022 by the American Society of Nephrology.
PY - 2022/10/27
Y1 - 2022/10/27
N2 - Key Points In heme protein-induced AKI, mitochondrial functional integrity, as reflected by ATP and NAD + content and NAD + /NADH ratio, is impaired. Mitochondrial quality control is compromised as reflected by impaired biogenesis, exaggerated fission, and marked ultrastructural damage. Modern concepts regarding mitochondria and AKI apply to heme protein-induced AKI, with the possibility of novel therapeutic strategies. Background Mitochondrial injury occurs in and underlies acute kidney injury (AKI) caused by ischemia-reperfusion and other forms of renal injury. However, to date, a comprehensive analysis of this issue has not been undertaken in heme protein-induced AKI (HP-AKI). We examined key aspects of mitochondrial function, expression of proteins relevant to mitochondrial quality control, and mitochondrial ultrastructure in HP-AKI, along with responses to heme in renal proximal tubule epithelial cells. Methods The long-established murine glycerol model of HP-AKI was examined at 8 and 24 hours after HP-AKI. Indices of mitochondrial function (ATP and NAD +), expression of proteins relevant to mitochondrial dynamics, mitochondrial ultrastructure, and relevant gene/protein expression in heme-exposed renal proximal tubule epithelial cells in vitro were examined. Results ATP and NAD + content and the NAD + /NADH ratio were all reduced in HP-AKI. Expression of relevant proteins indicate that mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) and fusion (MFN2) were impaired, as was expression of key proteins involved in the integrity of outer and inner mitochondrial membranes (VDAC, Tom20, and Tim23). Conversely, marked upregulation of proteins involved in mitochondrial fission (DRP1) occurred. Ultrastructural studies, including novel 3D imaging, indicate profound changes in mitochondrial structure, including mitochondrial fragmentation, mitochondrial swelling, and misshapen mitochondrial cristae; mitophagy was also observed. Exposure of renal proximal tubule epithelial cells to heme in vitro recapitulated suppression of PGC-1α (mitochondrial biogenesis) and upregulation of p-DRP1 (mitochondrial fission). Conclusions Modern concepts pertaining to AKI apply to HP-AKI. This study validates the investigation of novel, clinically relevant therapies such as NAD + -boosting agents and mitoprotective agents in HP-AKI.
AB - Key Points In heme protein-induced AKI, mitochondrial functional integrity, as reflected by ATP and NAD + content and NAD + /NADH ratio, is impaired. Mitochondrial quality control is compromised as reflected by impaired biogenesis, exaggerated fission, and marked ultrastructural damage. Modern concepts regarding mitochondria and AKI apply to heme protein-induced AKI, with the possibility of novel therapeutic strategies. Background Mitochondrial injury occurs in and underlies acute kidney injury (AKI) caused by ischemia-reperfusion and other forms of renal injury. However, to date, a comprehensive analysis of this issue has not been undertaken in heme protein-induced AKI (HP-AKI). We examined key aspects of mitochondrial function, expression of proteins relevant to mitochondrial quality control, and mitochondrial ultrastructure in HP-AKI, along with responses to heme in renal proximal tubule epithelial cells. Methods The long-established murine glycerol model of HP-AKI was examined at 8 and 24 hours after HP-AKI. Indices of mitochondrial function (ATP and NAD +), expression of proteins relevant to mitochondrial dynamics, mitochondrial ultrastructure, and relevant gene/protein expression in heme-exposed renal proximal tubule epithelial cells in vitro were examined. Results ATP and NAD + content and the NAD + /NADH ratio were all reduced in HP-AKI. Expression of relevant proteins indicate that mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) and fusion (MFN2) were impaired, as was expression of key proteins involved in the integrity of outer and inner mitochondrial membranes (VDAC, Tom20, and Tim23). Conversely, marked upregulation of proteins involved in mitochondrial fission (DRP1) occurred. Ultrastructural studies, including novel 3D imaging, indicate profound changes in mitochondrial structure, including mitochondrial fragmentation, mitochondrial swelling, and misshapen mitochondrial cristae; mitophagy was also observed. Exposure of renal proximal tubule epithelial cells to heme in vitro recapitulated suppression of PGC-1α (mitochondrial biogenesis) and upregulation of p-DRP1 (mitochondrial fission). Conclusions Modern concepts pertaining to AKI apply to HP-AKI. This study validates the investigation of novel, clinically relevant therapies such as NAD + -boosting agents and mitoprotective agents in HP-AKI.
KW - HP-AKI
KW - NAD
KW - acute kidney injury and ICU nephrology
KW - basic science
KW - hemeproteins
KW - mitochondria
KW - mitochondrial dynamics
KW - murine model
KW - organelle biogenesis
UR - http://www.scopus.com/inward/record.url?scp=85162767508&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85162767508&partnerID=8YFLogxK
U2 - 10.34067/KID.0004832022
DO - 10.34067/KID.0004832022
M3 - Article
C2 - 36514726
AN - SCOPUS:85162767508
SN - 2641-7650
VL - 3
SP - 1672
EP - 1682
JO - Kidney360
JF - Kidney360
IS - 10
ER -