PMID- 34948056
OWN - NLM
STAT- MEDLINE
DCOM- 20220201
LR  - 20231108
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 24
DP  - 2021 Dec 9
TI  - The Mechanism of Mitochondrial Injury in Alpha-1 Antitrypsin Deficiency Mediated 
      Liver Disease.
LID - 10.3390/ijms222413255 [doi]
LID - 13255
AB  - Alpha-1 antitrypsin deficiency (AATD) is caused by a single mutation in the 
      SERPINA1 gene, which culminates in the accumulation of misfolded alpha-1 
      antitrypsin (ZAAT) within the endoplasmic reticulum (ER) of hepatocytes. AATD is 
      associated with liver disease resulting from hepatocyte injury due to 
      ZAAT-mediated toxic gain-of-function and ER stress. There is evidence of 
      mitochondrial damage in AATD-mediated liver disease; however, the mechanism by 
      which hepatocyte retention of aggregated ZAAT leads to mitochondrial injury is 
      unknown. Previous studies have shown that ER stress is associated with both high 
      concentrations of fatty acids and mitochondrial dysfunction in hepatocytes. Using 
      a human AAT transgenic mouse model and hepatocyte cell lines, we show abnormal 
      mitochondrial morphology and function, and dysregulated lipid metabolism, which 
      are associated with hepatic expression and accumulation of ZAAT. We also describe 
      a novel mechanism of ZAAT-mediated mitochondrial dysfunction. We provide evidence 
      that misfolded ZAAT translocates to the mitochondria for degradation. 
      Furthermore, inhibition of ZAAT expression restores the mitochondrial function in 
      ZAAT-expressing hepatocytes. Altogether, our results show that ZAAT aggregation 
      in hepatocytes leads to mitochondrial dysfunction. Our findings suggest a 
      plausible model for AATD liver injury and the possibility of mechanism-based 
      therapeutic interventions for AATD liver disease.
FAU - Khodayari, Nazli
AU  - Khodayari N
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Wang, Rejean L
AU  - Wang RL
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Oshins, Regina
AU  - Oshins R
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Lu, Yuanqing
AU  - Lu Y
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Millett, Michael
AU  - Millett M
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Aranyos, Alek M
AU  - Aranyos AM
AUID- ORCID: 0000-0002-3130-1573
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Mostofizadeh, Sayedamin
AU  - Mostofizadeh S
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of 
      Florida, Gainesville, FL 32610, USA.
FAU - Scindia, Yogesh
AU  - Scindia Y
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Flagg, Tammy O
AU  - Flagg TO
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Brantly, Mark
AU  - Brantly M
AUID- ORCID: 0000-0003-0189-1565
AD  - Division of Pulmonary, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
LA  - eng
GR  - F007320/Alpha One/
PT  - Journal Article
DEP - 20211209
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (SERPINA1 protein, human)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Disease Models, Animal
MH  - Endoplasmic Reticulum Stress
MH  - Gain of Function Mutation
MH  - Gene Expression Profiling
MH  - Hepatocytes/*cytology/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Protein Transport
MH  - Proteolysis
MH  - Sequence Analysis, RNA
MH  - alpha 1-Antitrypsin/chemistry/*genetics/*metabolism
MH  - alpha 1-Antitrypsin Deficiency/genetics/metabolism/*pathology
PMC - PMC8704552
OTO - NOTNLM
OT  - alpha-1 antitrypsin deficiency
OT  - lipid droplets
OT  - mitochondrial injury
OT  - protein misfolding
COIS- The authors declare that they have no competing interests.
EDAT- 2021/12/25 06:00
MHDA- 2022/02/02 06:00
PMCR- 2021/12/09
CRDT- 2021/12/24 01:16
PHST- 2021/10/30 00:00 [received]
PHST- 2021/12/03 00:00 [revised]
PHST- 2021/12/07 00:00 [accepted]
PHST- 2021/12/24 01:16 [entrez]
PHST- 2021/12/25 06:00 [pubmed]
PHST- 2022/02/02 06:00 [medline]
PHST- 2021/12/09 00:00 [pmc-release]
AID - ijms222413255 [pii]
AID - ijms-22-13255 [pii]
AID - 10.3390/ijms222413255 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Dec 9;22(24):13255. doi: 10.3390/ijms222413255.