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.
Highlights
The dynamic behavior of mitochondria that constantly divide and fuse is pivotal to maintain their pleiotropic activities and their distribution within cells
The functional integrity of mitochondria depends on fusion and fission of their membranes, which maintain a dynamic mitochondrial network in cells
Interference with these processes causes neurodegenerative disorders that are characterized by axonal degeneration of distinct neurons
Summary
The dynamic behavior of mitochondria that constantly divide and fuse is pivotal to maintain their pleiotropic activities and their distribution within cells. Conserved protein machineries in the outer and inner membrane of mitochondria mediate membrane fusion events, ensure cristae formation and regulate the interaction of mitochondria with the endoplasmic reticulum [1,2,3]. Loss of mitochondrial fusion leads to neuronal loss in mice, highlighting the vulnerability of neurons for deficiencies in mitochondrial dynamics [4,5,6]. Mutations in the dynamin-like GTPases MFN2 and OPA1, which mediate mitochondrial membrane fusion, cause neurodegeneration in Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively [7,8,9]. Recent evidence identified prohibitins in the mitochondrial inner membrane as novel modulators of mitochondrial fusion [13,14,15]. The genetic interaction of yeast PHB1 and PHB2 with genes involved in the mitochondrial cardiolipin and phosphatidyl ethanolamine metabolism suggests
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