PHB2 forms a mitochondrial calcium channel that drives Parkinson’s disease

Dysregulated mitochondrial Ca2+ influx is a unifying driver of neurodegeneration, compromising neuronal bioenergetics and survival. In Parkinson’s disease (PD), impaired mitochondrial Ca2+ uptake is a decisive trigger for dopaminergic (DA) neuron loss, yet the molecular identity of the responsible channel has remained unresolved. Although the mitochondrial Ca2+ uniporter (MCU) is regarded as the principal conduit, global MCU ablation is non-lethal and MCU-deficient neurons retain basal Ca2+ uptake, pointing to the existence of a vital alternative pathway. Here we identify prohibitin2 (PHB2) forms this long-sought MCU-independent Ca2+ channel. Conditional ablation of PHB2 in DA neurons of mice induces hallmark PD pathology, including >70% substantia nigra neuron loss and severe motor deficits. By integrating live-cell mitochondrial Ca2+ imaging, mitoplast patch-clamp, single-molecule photometry, and high-field solution NMR, we demonstrate that PHB2 oligomerizes into a hexameric Ca2+ channel (~30 Å lumen). Structure-guided mutagenesis of four pore-lining residues abolished Ca2+ conductance, and this disruption of PHB2 channel function in DA neurons drives degeneration. Crucially, rescue experiments by adeno-associated virus mediated re-expression of wild-type PHB2, but not channel-dead mutant, in PHB2-DA-knockout mice restores >80% of DA neurons and reverses motor deficits. These findings identify PHB2 as the essential mitochondrial Ca2+ channel sustaining dopaminergic survival and nigral integrity, resolve a central enigma in mitochondrial biology, and establish the PHB2 pore as a tractable therapeutic target in PD. More broadly, modulation of PHB2 channel activity may represent a general strategy to reinforce mitochondrial resilience across neurodegenerative diseases.