Disassembly of mitochondrial cristae architecture drives neurodegeneration in Huntington’s disease

Background Mitochondrial dysfunction is a key feature of many neurodegenerative diseases, including Huntington’s disease (HD), yet the initiating cellular lesion that links the disease-causing protein, mutant huntingtin (mtHtt), to organelle failure and neuronal degeneration remains unclear. Methods Using complementary in vitro and in vivo models of HD, we investigated the molecular mechanisms by which mtHtt disrupts mitochondrial integrity and identified its mitochondrial target whose perturbation leads to cristae disorganization and subsequent neuronal degeneration. The pathogenic relevance of this pathway was further evaluated in HD patient iPSC-derived striatal neurons and HD knock-in mice through genetic manipulation, where behavioral assays, neuropathological analyses, and electron microscopy were employed to assess disease progression and mitochondrial ultrastructure. Results We show that mutant huntingtin (mtHtt) destabilizes mitochondrial membrane architecture through disruption of the mitochondrial contact site and cristae organizing system (MICOS). Across neuronal and mouse models HD, the MICOS complex is disassembled and its core scaffold protein mitofilin is depleted. Mechanistically, mtHtt accumulates at mitochondrial contact sites, associates with mitofilin, and recruits the AAA-ATPase VCP/p97, which drives ATPase-dependent extraction of mitofilin from MICOS, leading to cristae disorganization, respiratory impairment, and structural destabilization. Extracted mitofilin accumulates in insoluble assemblies with mtHtt and VCP, reducing the soluble pool required to maintain crista junctions. Blocking VCP mitochondrial recruitment or inhibiting its ATPase activity preserves MICOS integrity, while restoring mitofilin reconstitutes cristae architecture, improves mitochondrial and synaptic function in patient-derived neurons, and ameliorates neuropathology and motor deficits in HD mice. Conclusions These findings identify mitochondrial cristae architecture as a point of vulnerability in neurodegeneration and establish architectural destabilization of organelles as an upstream pathogenic mechanism linking disease proteins to neuronal degeneration.