Misfolded alpha-1 antitrypsin (ZAAT) protein accumulation leads to mitochondrial damage, a new study published in the International Journal of Molecular Sciences found. ZAAT is the hallmark of alpha-1 antitrypsin deficiency (AATD) within the hepatocytes.

It was already known that liver disease in AATD was associated with mitochondrial damage. However, the mechanism of how this occurred was not clear.

Here, a team of researchers led by Mark Brantly, MD, from the Department of Medicine at the University of Florida in Gainesville shed light on the mechanism by which ZAAT aggregation inside hepatocytes leads to mitochondrial injury.

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“Our findings suggest a plausible model for AATD liver injury and the possibility of mechanism-based therapeutic interventions for AATD liver disease,” they wrote.

Read more about AATD etiology

Using a transgenic mouse model of human AAT and hepatocyte cell lines, the researchers showed that ZAAT aggregation led to abnormal mitochondrial morphology and function. They said this was because ZAAT translocates to the mitochondria for degradation. 

Inhibiting the expression of ZAAT in hepatocytes grown in culture restored mitochondrial function, the researchers said. Together these findings provide a novel mechanism of how ZAAT leads to mitochondrial dysfunction, and the researchers also showed that ZAAT aggregation dysregulated lipid metabolism.

“Altogether, our results show that ZAAT aggregation in hepatocytes leads to mitochondrial dysfunction,” they concluded. “A better understanding of the influence of the proposed mechanisms will reveal the importance of mitochondrial dynamics for the progression of liver injury mediated by misfolded ZAAT.”

AATD is caused by a mutation in the SERPINA1 gene, which causes the AAT protein to misfold. Misfolded AAT cannot leave the liver and therefore accumulates inside hepatocytes causing damage.

The role of the AAT protein is to protect the lungs from neutrophil elastase. Since it cannot leave the liver, ZAAT then also can’t reach the lungs, and patients with AATD then develop lung diseases such as emphysema, chronic obstructive pulmonary disease, and chronic bronchitis in addition to liver disease.


Khodayari N, Wang RL, Oshins R, et al. The mechanism of mitochondrial injury in alpha-1 antitrypsin deficiency mediated liver disease. Int J Mol Sci. 2021;22(24):13255. doi:10.3390/ijms222413255