Role of frataxin in liver injury

Emory University, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY Metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of liver diseases from simple steatosis to, steatohepatitis, hepatic fibrosis, and cirrhosis, is the most common liver disease in the United States and worldwide. There are currently limited treatment options for MASLD because of our poor understanding of its pathogenesis. Dysfunction of the mitochondria induces disrupted lipid metabolism, oxidative stress, and hepatocyte death. While compelling evidence indicates a central role of mitochondrial dysfunction in the development and progression of MASLD, the underlying cause of mitochondrial dysfunction remains elusive. Iron is essential for cell metabolism dependent on the biogenesis of iron sulfur clusters (ISCs) and heme, essential cofactors for enzymes in the citric acid cycle and mitochondrial respiration chain. Impaired iron utilization, as seen in Friedrich’s ataxia (FRDA) due to the loss-of-function of mutations in frataxin (FXN), leads to ISC deficiency and mitochondrial free iron overload (MFIO). Nevertheless, the potential role of FXN has never been examined in metabolic diseases including the MASLD. Our preliminary study identified for the first time a markedly decreased expression of FXN in mouse and human specimens of MASLD. We have also observed hepatic MFIO and ferroptosis in a chronic mouse model of MASLD. Additional data showed a protective role of FXN against liver injury in an acute model of MASLD. We therefore hypothesize that steatosis-induced downregulation of FXN disrupts mitochondrial function and lipid metabolism and induces MFIO-dependent hepatocyte ferroptosis, which collectively promote the development of steatohepatitis. Specific Aim 1 will interrogate whether FXN deficiency induces while restoration of FXN expression prevents ferroptosis-mediated liver injury related to MASLD. We also aim to unravel a ferroptosis-specific mechanism that triggers liver inflammatory responses. Specific Aim 2 will determine the precise mechanism by which MFIO triggers lipid peroxidation in the plasma membrane ultimately leading to ferroptosis, with a focus on labile iron dynamics through real-time confocal fluorescence imaging. Specific Aim 3 will identify the critical role of steatosis- associated ER stress response in the induction of hepatic FXN protein degradation in mice and humans with MASLD. A temporospatial changes in FXN expression at the different disease phases of MASLD will be also determined. Successful completion of the proposed studies will unveil that FXN-dependent defects in mitochondrial iron metabolism is a novel mechanism of mitochondrial dysfunction and ferroptosis-mediated liver injury in MASLD, laying the foundation for developing potential new therapies.