Mitochondrial depletion of glutaredoxin 2 induces metabolic dysfunction-associated fatty liver disease in mice
Valeria Scalcon,
Alessandra Folda,
Maria Giovanna Lupo,
Federica Tonolo,
Naixuan Pei,
Ilaria Battisti,
Nicola Ferri,
Giorgio Arrigoni,
Alberto Bindoli,
Arne Holmgren,
Lucia Coppo,
Maria Pia Rigobello
Affiliations
Valeria Scalcon
Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy
Alessandra Folda
Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy
Maria Giovanna Lupo
Department of Medicine, University of Padova, 35121, Padova, Italy
Federica Tonolo
Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy
Naixuan Pei
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17165, Stockholm, Sweden
Ilaria Battisti
Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy; Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, 35129, Padova, Italy
Nicola Ferri
Department of Medicine, University of Padova, 35121, Padova, Italy
Giorgio Arrigoni
Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy; Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, 35129, Padova, Italy
Alberto Bindoli
Institute of Neuroscience, CNR c/o Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy
Arne Holmgren
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17165, Stockholm, Sweden
Lucia Coppo
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17165, Stockholm, Sweden; Corresponding author.
Maria Pia Rigobello
Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy; Corresponding author.
Glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase that facilitates glutathionylation/de-glutathionylation of target proteins. The main variants of Grx2 are the mitochondrial Grx2a and the cytosolic Grx2c. The aim of this study was to investigate the specific role of mitochondrial Grx2 in vivo using a mitochondrial Grx2 depleted (mGD) mouse model. mGD mice displayed an altered mitochondrial morphology and functioning. Furthermore, the lack of Grx2 in the mitochondrial compartment is responsible for increased blood lipid levels under a normal diet, a metabolic dysfunction-associated fatty liver disease (MAFLD) phenotype and a decreased glycogen storage capacity. In addition, depleting Grx2a leads to an alteration in abundance and in glutathionylation pattern of different mitochondrial enzymes, highlighting the selective role of Grx2 in the regulation of metabolic pathways. Overall, our findings identify the involvement of mitochondrial Grx2a in the regulation of cell metabolism and highlight a previously unknown association between Grx2 and MAFLD.
