Schizophyllan (SPG), produced by Schizophyllum commune, is an exopolysaccharide with multiple academic and commercial uses, including in the food industry and for various medical functions. We previously demonstrated that SPG conjugated with c-
Src peptide exerted a significant
therapeutic effect on mouse models of the acute inflammatory diseases polymicrobial
sepsis and
ulcerative colitis. Here we extended these results by investigating whether SPG exerted a protective effect against mitochondrial damage in the liver via
sirtuin 3 (
SIRT3) induction, focusing on the deacetylation of
succinate dehydrogenase A (SDHA) and
superoxide dismutase 2 (SOD2). Liver damage models induced by alcohol or
conjugated linoleic acid (CLA, which simulates
lipodystrophy) in
SIRT3-/-, SOD2-/-, and SDHA-/- mice were used. Results showed that dietary supplementation with SPG induced
SIRT3 activation; this was involved in mitochondrial metabolic
resuscitation that countered the adverse effects of
alcoholic liver disease and CLA-induced damage. The mitochondrial
SIRT3 mediated the deacetylation and activation of SOD2 in the liver and SDHA in adipose tissues, suggesting that SPG supplementation reduced
ethanol-induced liver damage and CLA-induced adverse dietary effects via SIRT3-SOD2 and SIRT3-SDHA signaling, respectively. Together, these results suggest that dietary SPG has a previously unrecognized role in SIRT3-mediated mitochondrial metabolic
resuscitation during mitochondria-related diseases.