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Prohibitin 1 (PHB1) is a multifunction protein that is released in lipid droplets from adipocytes and possibly other cells and is detectable in the circulation. PHB1 is also involved in mitochondrial biogenesis and function. Recently we have reported that PHB1 has a previously unrecognized role as an inhibitor of pyruvate carboxylase (FEBS Journal 273 (2006) 568-576). As a consequence, it can modulate mitochondrial fuel metabolism which play important role in insulin secretion. In the present study we used crosslinking, immunoprecipitation and proteomic analysis to investigate binding partners for circulating PHB1. Crosslinking of PHB1 to serum resulted in two complexes of ∼ 150 and 100 kDa which contained both PHB1 and fragments of complement 3 (C3). The binding of PHB1 to C3 was confirmed using a solid phase assay where the dissociation constant was ∼ 90 fmol/L. PHB1, but not the closely related PHB2, was able to enhance complement activation and induce lysis of sensitized sheep erythrocytes when added with normal serum but not with C3-deficient serum. The ability of PHB1 to bind to, and activate C3 suggests that PHB1 may have a previously unrecognized role in innate immunity. Complement is important in fighting infection and low grade inflammation which has been documented in elderly and diabetic subjects, may by activating complement, increases delivery of PHB1 to tissues. On the basis of our observations we hypothesized that PHB1 may be a potential link between activated acute phase response and pathogenesis of type 2 diabetes. [ABSTRACT FROM AUTHOR]