The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease

Abstract

Although originally identified as putative negative regulators of the cell cycle, recent studies have demonstrated that the PHB proteins act as a chaperone in the assembly of subunits of mitochondrial respiratory chain complexes. The two PHB proteins, Phblp and Phb2p, are located in the mitochondrial inner membrane where they form a large complex that represents a novel type of membrane-bound chaperone. On the basis of its native molecular weight, the PHB-complex should contain 12-14 copies of both Phblp and Phb2p. The PHB complex binds directly to newly synthesised mitochondrial translation products and stabilises them against degradation by membrane-bound metalloproteases belonging to the family of mitochondrial triple-A proteins. Sequence homology assigns Phb1p and Phb2p to a family of proteins which also contains stomatins, HflKC, flotillins and plant defence proteins. However, to date only the bacterial HflKC proteins have been shown to possess a direct functional homology with the PHB complex. Previously assigned actions of the PHB proteins, including roles in tumour suppression, cell cycle regulation, immunoglobulin M receptor binding and apoptosis seem unlikely in view of any hard evidence in their support. Nevertheless, because the proteins are probably indirectly involved in ageing and cancer, we assess their possible role in these processes. Finally, we suggest that the original name for these proteins, the prohibitins, should be amended to reflect their roles as proteins that hold badly formed subunits, thereby keeping the nomenclature already in use but altering its meaning to reflect their true function more accurately.

Ancient origin of reggie (flotillin), reggie-like, and other lipid-raft proteins: convergent evolution of the SPFH domain

“…2B). Prohibitin-1 (Phb-1) and -2 (Phb-2) are two ubiquitous, abundant and highly conserved proteins that play important roles as chaperones during the assembly of mitochondrial respiratory chain complexes [42,43]. They are 130 to 157 aa shorter than reggies/flotillins and consist of a single SPFH domain located at their N terminus (human Phb-1 residues 26-187; fig.…”

“…2B). Prohibitins have an N-terminal transmembrane stretch (Phb-1 residues 11-23) preceding the SPFH domain that is cleaved off in the mature peptide, and a putative phosphorylation site at Tyr-259 [43]. Available 3D structures for human Phb-1 (1lu7.pdb model) indicate that this protein folds very differently to the SPFH domain of reggies/flotillins ( fig.…”

“…algae) or lower eukaryotes, their presence in fungi and higher plants is surprising, and raises the scenario of an early symbiotic gene transfer between these two taxa [48]. The absence of viral, archaeal or lower eukaryotic reggielike genes contrasts with the situation for other SPFH superfamily members (stomatin or prohibitin), which have been recorded in a wider range of organisms [43,49], and in some cases greatly expanded by gene duplication, such as the six stomatin genes of the nematode C. elegans ( fig. 6).…”

Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: Possible involvement of mitochondrial S-adenosylmethionine transport

“…Furthermore, it has been shown that the decrease in PHB1 levels correlates with a loss of mitochondrial function [48]. PHB1 functions as a chaperone-like protein for the correct folding and assembly of subunits of the mitochondrial respiratory-chain complexes, and it must be methylated inside the mitochondria before it functions [49]. Therefore, mitochondrial SAM depletion could affect electron transfer along the mitochondrial respiratory-chain and result in oxidative stress inside mitochondria, representing another possible mechanism involved in sensitization to TNF hepatotoxicity by intracellular SAH accumulation.…”

Prohibitin promotes androgen receptor activation in ER-positive breast cancer

“…[1][2][3][4] PHB has been reported to repress E2F via recruitment of the repressive proteins histone deacetylase 1 (HDAC1), nuclear receptor co-repressor (N-CoR) and the chromatin-condensing proteins brahma-related gene-1 (BRG1)/brahma (Brm). 5,6 PHB can also inhibit steroidactivated nuclear receptors, such as the androgen receptor (AR) and estrogen receptor (ER).…”