MNDA regulates a novel nuclear‐mitochondrial circuit critical for progression of apoptosis in human neutrophils

Abstract

Delayed neutrophil apoptosis perpetuates inflammation and delays the resolution of inflammation. We investigated the role of the nuclear protein MNDA (myeloid nuclear differentiation antigen) in progression of apoptosis of human neutrophils. We found that during constitutive apoptosis, MNDA is cleaved by caspase‐3 and relocated from the nucleus to the cytoplasm. MNDA co‐immunoprecipitates with the anti‐apoptotic protein Mcl‐1, accelerates proteasomal degradation of Mcl‐1, thereby contributing to collapse of mitochondrial transmembrane potential. MNDA knockdown with short hairpin RNA attenuates Mcl‐1 turnover, preserve mitochondrial function and confers resistance to apoptosis in myeloid HL‐60 cells. Culture of neutrophils with inflammatory mediators, including LPS, bacterial DNA, PAF or the acute phase reactants modified C‐reactive protein and serum amyloid A, prevents MNDA cleavage and translocation parallel with suppression of neutrophil apoptosis. Our results identify MNDA as a central mediator of a novel nucleus‐mitochondrion circuit that regulates progression of neutrophil apoptosis. (Grant support: LLSC and CIHR).