Connecting mitochondrial defects to reduced autophagy in metabolic liver diseases through FATP2.

Hepatic mitochondrial dysfunction is a common clinical feature of several metabolic disorders, including type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH).

Mitofusin 2 (MFN2), a transmembrane protein necessary for mitochondria-endoplasmic reticulum tethering, is decreased in T2D and NASH.

Moreover, its liver-specific ablation promotes the manifestation of NASH and increases the susceptibility to developing liver cancer in mice. Recently, the Zorzano lab has identified several interactors of MFN2 involved in lipid transport.

The ""MITOTUA"" project focuses on the study of FATP2, a fatty acid transporter/acyl-CoA synthetase predicted to participate in mitochondria-associated autophagosome formation during starvation.

We plan to perform a battery of in vitro and in vivo experiments to properly characterize the mechanistic implications of MFN2-FATP2 interaction to autophagy activation and mitochondrial function.

The ""MITOTUA"" project will also investigate the relevance of FATP2 to the hepatic alterations connected to the metabolic syndrome by using murine models of liver steatosis (ob/ob and db/db mice) and NASH (CDAHFD diet) and analyzing liver biopsies of patients with fatty liver disease.

The combination of my strong background in complex metabolic syndromes and the well-recognized expertise of the Zorzano lab in the study of autophagy and mitochondrial metabolism will undoubtedly result in a well-conducted scientific project and a successful reciprocal transfer of knowledge.

Overall, this fellowship represents a unique opportunity to enroll in a prolific research group of a distinguished institution, taking advantage of an ecosystem shaped to maximize the potential of this proposal and acquire new competencies that complement my scientific preparation, reaching the professional maturity necessary to become an independent researcher in the forthcoming years.