Themis Thoudam, PhD

Travel Award
$1,500

Indiana University

PDK4-Mediated SEPT2 Phosphorylation Drives Mitochondrial Dysfunction in Alcohol-Associated Liver Disease via promoting mitochondrial fission

Mentor: Suthat Liangpunsakul, MD

Alcohol-associated liver disease (ALD) is a major global health burden and one of the leading causes of liver-related morbidity and mortality worldwide. Despite its prevalence, the molecular mechanisms driving ALD progression remain incompletely understood. Mitochondrial dysfunction, particularly excessive mitochondrial fragmentation, is a hallmark of ALD, contributing to impaired energy metabolism and increased production of reactive oxygen species (ROS), which exacerbate liver injury.

Our recent work has identified pyruvate dehydrogenase kinase 4 (PDK4) as a critical regulator of mitochondrial fragmentation in ALD. Specifically, PDK4 phosphorylates Septin 2 (SEPT2) at serine 218, a modification that enhances the interaction between SEPT2 and Dynamin-related protein 1 (DRP1), the key mediator of mitochondrial fission. This PDK4 -SEPT2 -DRP1 signaling axis drives excessive mitochondrial fragmentation, leading to oxidative stress and hepatocellular damage.

In this study, we demonstrated that alcohol exposure in a mouse model of ALD significantly increased mitochondrial fragmentation, upregulated PDK4 expression, and elevated SEPT2 phosphorylation at serine 218. These changes promoted DRP1 recruitment to mitochondria, facilitating fragmentation. Notably, similar alterations were observed in liver tissues from ALD patients, underscoring the clinical relevance of this pathway. In cultured hepatocytes, alcohol enhanced SEPT2 phosphorylation and its interaction with DRP1, whereas expression of a phosphorylation-deficient SEPT2 mutant disrupted DRP1 binding and reduced mitochondrial fragmentation. Hepatocytes lacking PDK4 were resistant to alcohol-induced mitochondrial dysfunction, showing decreased fragmentation and ROS production.

These findings suggest that targeting PDK4 may represent a promising therapeutic strategy for ALD.