Mitochondrial HKDC1 suppresses oxidative stress and apoptosis by regulating mitochondrial function in goose fatty liver

Different from human non-alcoholic fatty liver disease (NAFLD), goose fatty liver is physiological with no inflammation. Consistently, mitochondrial dysfunction, oxidative stress and apoptosis are rarely seen in goose fatty liver. Hexokinase domain-containing protein 1 (HKDC1) is involved in maintaining systemic glucose homeostasis, and its absence causes mitochondrial dysfunction. Here, we demonstrated that mitochondrial outer membrane-bound HKDC1 (mHKDC1) had an expression pattern different from that of whole-cell HKDC1 (wHKDC1). Data indicated that the protein level of whole-cell HKDC1 (wHKDC1) was increased but mHKDC1 was decreased in mouse fatty liver. Interestingly, both the protein levels of wHKDC1 and mHKDC1 were significantly increased in goose fatty liver. Treatment of goose or mouse hepatocytes with fatty liver-related factors could influence the expression of wHKDC1 and mHKDC1, but the influence on wHKDC1 was not identical to mHKDC1. HKDC1 overexpression in goose hepatocytes increased wHKDC1 and mHKDC1 expression, mitochondrial membrane potential (MMP), mitochondrial respiratory chain activity, and suppressed reactive oxygen species (ROS) generation, apoptosis and cytokine-cytokine receptor signaling pathway. In addition, mutations in mitochondrial signal peptide or activation domain of HKDC1 altered MMP or ROS levels. In conclusion, HKDC1, particularly mHKDC1, may protect goose fatty liver by regulating mitochondrial function, ROS generation, apoptosis, and inflammation-related pathways.