Prohibitins and the functional compartmentalization of mitochondrial membranes

Abstract

Prohibitins constitute an evolutionarily conserved and ubiquitously expressed family of membrane proteins that are essential for cell proliferation and development in higher eukaryotes. Roles for prohibitins in cell signaling at the plasma membrane and in transcriptional regulation in the nucleus have been proposed, but pleiotropic defects associated with the loss of prohibitin genes can be largely attributed to a dysfunction of mitochondria. Two closely related proteins, prohibitin-1 (PHB1) and prohibitin-2 (PHB2), form large, multimeric ring complexes in the inner membrane of mitochondria. The absence of prohibitins leads to an increased generation of reactive oxygen species, disorganized mitochondrial nucleoids, abnormal cristae morphology and an increased sensitivity towards stimuli-elicited apoptosis. It has been found that the processing of the dynamin-like GTPase OPA1, which regulates mitochondrial fusion and cristae morphogenesis, is a key process regulated by prohibitins. Furthermore, genetic analyses in yeast have revealed an intimate functional link between prohibitin complexes and the membrane phospholipids cardiolipin and phosphatidylethanolamine. In light of these findings, it is emerging that prohibitin complexes can function as protein and lipid scaffolds that ensure the integrity and functionality of the mitochondrial inner membrane.

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation

“…Prohibitins are ubiquitous, evolutionarily conserved proteins that are mainly localized in mitochondria. PHB2 has a predominantly mitochondrial function and it is related to mitochondrial network and apoptosis 26 . Deletion of PHB2 leads to an aberrant cristae morphogenesis and an impaired cellular proliferation and resistance towards apoptosis 14 .…”

Prohibitin-2 Binding Modulates Insulin-like Growth Factor-binding Protein-6 (IGFBP-6)-induced Rhabdomyosarcoma Cell Migration

“…PHB1 and -2 are highly conserved membrane proteins that act interdependently (20 -22, 39) by forming ring complexes that serve as protein scaffolds and chaperones in mitochondria (8,21). However, some actions and protein interactions are specific to PHB1 or PHB2.…”

“…PHBs modulate signaling pathways (19), including MAPK pathways, and affect apoptosis, proliferation, adhesion, and migration in a cell-and context-specific manner. They are found in mitochondria, nuclei, and cell membranes and translocate between these sites (8). In particular, PHBs may be functional on the cell surface.…”

“…They have diverse functions. For example, PHB1 and PHB2 form large ring complexes in the inner mitochondrial membrane and function as chaperone proteins that stabilize mitochondrial respiratory enzymes and maintain mitochondrial integrity (8,9). In the nucleus, PHBs serve as transcriptional regulators, thereby repressing cell proliferation (10).…”

Mitochondrial involvement in neurodegenerative diseases

“…In opposite to fast dividing cells, neurons (integrated in complex networks) cannot be simply eliminated by selection processes if they have compromised mitochondria. Neuronal mitochondria, therefore, need mechanisms to eliminate damaged proteins which occurs, for example, by the AAA (ATPase associated with diverse cellular activities) protease paraplegin (SPG7), which is mutated in hereditary spastic paraplegia (HSP) 7, but also by the paraplegin-related protease AFG3L2, which is mutated in SCA28 (23). Other routes for mitochondrial protein degradation exist also, because outer membrane proteins can be back transported into the cytosol for subsequent clearance by the proteasome with the mitochondrially targeted valosin-containing protein (VCP/p97, also a AAA protease (24)), which is mutated in a specific form of inherited amyotrophic lateral sclerosis (ALS).…”