Themis Thoudam, PhD

American Liver Foundation Postdoctoral Research Fellowship Award
$25,000 over one year

Indiana University

Mechanism of PDK4 in mitochondrial dynamics and mitochondrial function in alcohol-associated liver disease
Mentor: Suthat Liangpunsakul, MD, MPH

Alcohol-associated liver disease (ALD) is a significant global health problem and one of the leading causes of liver diseases in the US.  ALD is a complex disorder that occurs as a consequence of excessive alcohol use.  The pathogenesis of ALD is a complicated process leading to a spectrum of histopathological changes during the disease progression from hepatic steatosis, alcoholic hepatitis, and alcohol-associated cirrhosis.  Despite the success in exploring the therapy for other chronic liver diseases such as hepatitis C, the progress to identify therapeutic interventions for patients with ALD is quite static.  Understanding the mechanisms underlying the pathogenesis of ALD is important as this may pave a way for the discovery of targeted therapies for patients with ALD. 

Mitochondrial dysfunction is one of the major factors involved in the pathogenesis of alcohol-associated liver disease (ALD).  Mitochondria involves in nutrient and energy metabolism to regulate cellular homeostasis.  Mitochondrial dysfunction contributes to excessive intracellular reactive oxygen species (ROS) formation leading to the activation of stress signaling in the pathogenesis of ALD.  However, the key mechanistic pathway leading to mitochondrial dysfunction in ALD remains elusive.

To maintain its proper function, mitochondria undergo a dynamic transition between fission and fusion.  We have found that alcohol disrupts the balance between this dynamic transition and causes excessive fission during the pathogenesis of ALD.  We have identified a protein, pyruvate dehydrogenase kinase 4 (PDK4), as a key regulator in this process.  In this ALF postdoctoral fellow award, we proposed to mechanistically explore the underlying molecular mechanism of how PDK4 mediates mitochondrial fission and dysfunction in ALD.  The outcomes of this award will open an avenue to determine if PDK4 can be used as a target for the treatment of ALD.