Loss of Prohibitin Membrane Scaffolds Impairs Mitochondrial Architecture and Leads to Tau Hyperphosphorylation and Neurodegeneration

Abstract

Fusion and fission of mitochondria maintain the functional integrity of mitochondria and protect against neurodegeneration, but how mitochondrial dysfunctions trigger neuronal loss remains ill-defined. Prohibitins form large ring complexes in the inner membrane that are composed of PHB1 and PHB2 subunits and are thought to function as membrane scaffolds. In Caenorhabditis elegans, prohibitin genes affect aging by moderating fat metabolism and energy production. Knockdown experiments in mammalian cells link the function of prohibitins to membrane fusion, as they were found to stabilize the dynamin-like GTPase OPA1 (optic atrophy 1), which mediates mitochondrial inner membrane fusion and cristae morphogenesis. Mutations in OPA1 are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells, highlighting the importance of OPA1 function in neurons. Here, we show that neuron-specific inactivation of Phb2 in the mouse forebrain causes extensive neurodegeneration associated with behavioral impairments and cognitive deficiencies. We observe early onset tau hyperphosphorylation and filament formation in the hippocampus, demonstrating a direct link between mitochondrial defects and tau pathology. Loss of PHB2 impairs the stability of OPA1, affects mitochondrial ultrastructure, and induces the perinuclear clustering of mitochondria in hippocampal neurons. A destabilization of the mitochondrial genome and respiratory deficiencies manifest in aged neurons only, while the appearance of mitochondrial morphology defects correlates with tau hyperphosphorylation in the absence of PHB2. These results establish an essential role of prohibitin complexes for neuronal survival in vivo and demonstrate that OPA1 stability, mitochondrial fusion, and the maintenance of the mitochondrial genome in neurons depend on these scaffolding proteins. Moreover, our findings establish prohibitin-deficient mice as a novel genetic model for tau pathologies caused by a dysfunction of mitochondria and raise the possibility that tau pathologies are associated with other neurodegenerative disorders caused by deficiencies in mitochondrial dynamics.

Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria

“…We have previously described that apoptosis contributes to neuronal loss in Phb2 NKO mice, but have detected only a limited number of TUN EL-positive neurons (Merkwirth et al, 2012). Consistently, immunoblot analysis did not provide evidence of apoptotic or necrotic cell death or of altered autophagy in hippocampal lysates (Fig.…”

“…Neuronal loss is accompanied by the destabilization of L-OPA1, defects in mitochondrial ultrastructure, loss of mitochondrial DNA (mtDNA), and late-onset mitochondrial dysfunction (Merkwirth et al, 2012). Here, we demonstrate that ablation of Oma1 prevents loss of L-OPA1, delays neurodegeneration, and extends the lifespan of Phb2 NKO mice.…”

“…Neuronal loss in Phb2 NKO mice is accompanied by up-regulation of glial fibrillary acidic protein (GFAP) in astrocytes, already apparent at 6 wk of age (Merkwirth et al, 2012). Immunohistochemical and immunoblot analyses of the hippocampus of 14-wk-old Phb2 NKO mice revealed accumulation of GFAP and ionized calcium binding adaptor molecule 1 (IBA1), indicating astrogliosis and activated microglia, respectively (Fig.…”

“…We deleted Oma1 in mice lacking Phb2 specifically in forebrain neurons (Phb2 NKO ; Merkwirth et al, 2012) by crossing Phb2 NKO mice to Oma1 ko/ko mice (Quirós et al, 2012). Deletion of Phb2 resulted in premature death starting at the age of 16 wk, whereas control (Phb2 fl/fl ) and Oma1 ko/ko mice showed normal lifespans (Fig.…”

“…We thus reasoned that L-OPA1-independent neuronal functions of PHB2 limit the lifespan of Phb2 NKO Oma1 ko/ko mice. We have previously described respiratory defects in Phb2 NKO mice at late stages (Merkwirth et al, 2012). To examine whether OMA1 affects mitochondrial respiratory function in prohibitin-deficient neurons, we monitored Immunohistochemical staining of coronal sections across the hippocampal region from 14-wk-old mice using GFAP-and IBA1-specific antibodies.…”