Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria

Abstract

Prohibitins comprise an evolutionarily conserved and ubiquitously expressed family of membrane proteins with poorly described functions. Large assemblies of PHB1 and PHB2 subunits are localized in the inner membrane of mitochondria, but various roles in other cellular compartments have also been proposed for both proteins. Here, we used conditional gene targeting of murine Phb2 to define cellular activities of prohibitins. Our experiments restrict the function of prohibitins to mitochondria and identify the processing of the dynamin-like GTPase OPA1, an essential component of the mitochondrial fusion machinery, as the central cellular process controlled by prohibitins. Deletion of Phb2 leads to the selective loss of long isoforms of OPA1. This results in an aberrant cristae morphogenesis and an impaired cellular proliferation and resistance toward apoptosis. Expression of a long OPA1 isoform in PHB2-deficient cells suppresses these defects, identifying impaired OPA1 processing as the primary cellular defect in the absence of prohibitins. Our results therefore assign an essential function for the formation of mitochondrial cristae to prohibitins and suggest a coupling of cell proliferation to mitochondrial morphogenesis.

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

“…These data suggest that PHB2 can inhibit mitochondrial fission and apoptosis, and PHB2 may antagonize myocardial injury. Previous reports have shown that loss of prohibitins results in the fragmentation of the mitochondrial network in HeLa cells and MEFs 13,14 . The mitochondrial fragmentation of PHB2-depleted MEFs strikingly resembles the mitochondrial morphology observed after OPA1 downregulation 14,27 .…”

“…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 . This suggests that PHB2 may have an important role in regulating mitochondrial morphology.…”

“…PHB2 is mainly localized in the mitochondrial inner membrane and has an important role in regulating mitochondrial morphology. Recent findings suggest that loss of PHB2 results in accumulation of fragmented mitochondria in MEFs and HeLa cells 13,14 . However, the role of PHB2 in mitochondrial dynamics in the heart remains unknown.…”

Recent insights into the actions of IGFBP-6

“…PHB2 knockout resulted in early embryonic lethality (Park et al 2005), while PHB2 deletion impaired mouse embryonic fibroblast proliferation and increased their susceptibility to apoptotic stimuli (Merkwirth et al 2008). In breast cancer cells, nuclear PHB2 repressed the activity of estrogen receptor-α ).…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Pro-oncogenic alterations in MEK/ERK signalling pathway lead to phosphorylation of Mfn-1, increasing its affinity to and sequestering Bax, so preventing apoptosis [53]. In some human colon cancer cell lines, it has been shown that Drp1 favours tumor growth, since its depletion reduces Opa-1-L to Opa-1-S ratio, thereby promoting cytC release from the cristae and apoptosis [54].…”