Abstract 2384 Mitochondrial fission and extracellular mitochondria mediate liver damage in non-alcoholic fatty liver disease

Background: While mitochondrial dysfunction plays a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the underlying mechanisms have not been fully elucidated. Recently, impairments in mitochondrial dynamics have been shown to result in mitochondrial dysfunction and extracellular release of pro-inflammatory mitochondrial byproducts (exMito) in various disease models. In particular, inhibition of excessive mitochondrial fission has been shown to abrogate mitochondrial dysfunction and decreaseextracellular release of mitochondrial byproducts in pre-clinical models. Accordingly, we evaluated the role of excessive mitochondrial fission and associated exMito in the progression of NAFLD. Methods: C57BL6/J mice were subjected to a high-fat diet (HFD, 60% kcal% fat) for 13 weeks to induce NAFLD. Changes in key regulators of mitochondrial fission (DRP1,FIS1, MID49, MID51), mitochondrial function, hepatic function and cytokine profiles were evaluated. Simultaneously, exMito were collected and characterized from plasma. Using rationally designed peptide (P110), we determined the impact of pharmacologic inhibition of DRP1/FIS1 dependent mitochondrial fission on hepatic mitochondrial function as well as the quality and quantity of exMito. Results: Mice treated with HFD demonstrated key characteristics of metabolic syndrome including impaired glucose tolerance. Histologic evaluation of the liver demonstrated higher ectopic lipid accumulation and collagen deposition in HFD group, consistent with NAFLD. This was corroborated with plasma markers of liver damage. Furthermore, HFD group exhibited increased hepatic Drp1 protein expression and lipid peroxidation. HFD treated mice also demonstrated increased levels of exMito in circulation. Multiplex cytokine profiledemonstrated a significant pro-inflammatory shift following HFD treatment using a 48-plex Procarta Plex panel. Treatment of HFD mice with P110, improved mitochondrial function and glucose utilization, exMito release and subsequently improved liver injury. Conclusion: Inhibition of DRP1/FIS1 dependent mitochondrial fission reduced lipotoxicity-mediated mitochondrial dysfunction in the liver and decreased the release of exMito. This was associated with a decrease in pro-inflammatory response and improved hepatic architecture and function. Therefore, pathologic fission and exMito may play a critical role in NAFLD. This work was supported by the National Science and Technology Council (111-2917-I-564-014 and 112-2311-B-002-026) to SJL, Ministry of Education in Taiwan (108L4000) to SJL, American Heart Association (23POST1025911) to SJL and NICHD R00HD099387 to BH.