Mammalian prohibitin proteins respond to mitochondrial stress and decreaseduring cellular senescence

The two prohibitin proteins, Phb1p and Phb2p(BAP37) hare been ascribed vari ous functions, including cell cycle regulation, apoptosis, assembly of mito chondrial respiratory chain enzymes, and aging. We show that the mammalian prohibitins are present in the inner mitochondrial membrane and are always bound to each other, with no free protein detectable. They are coexpressed during development and in adult mammalian tissues, and expression levels ar e indicative of a role in mitochondrial metabolism, but are not compatible with roles in the regulation of cellular proliferation or apoptosis. High l evel expression of the proteins is consistently seen in primary human tumor s, while cellular senescence of human and chick fibroblasts is accompanied by heterogeneous decreases in both proteins. The two proteins are induced b y metabolic stress caused by an imbalance in the synthesis of mitochondrial - and nuclear-encoded mitochondrial proteins, but do not respond to oxidati ve stress, heat shock, or other cellular stresses. The gene promoter sequen ces contain binding sites for the Myc oncoprotein and overexpression of Myc induces expression of the prohibitins. The data support conserved roles fo r the prohibitins in regulating mitochondrial respiratory activity and in a ging. (C) 2001 Academic Press.