SAK3, a Cav3.1 enhancer facilitates mitochondrial function and neuronal survival in Parkinson’s disease models by modulating the SphK1/S1P signaling cascade

Parkinson’s disease (PD) involves dopaminergic neuron loss linked to calcium imbalance. Although calcium channel blockers have shown limited efficacy, SAK3 is a known selective enhancer of the T-type calcium channel Cav3.1. While it shows neuroprotective potential, its precise downstream mechanisms in Parkinson’s disease (PD) remain unclear. We found Cav3.1, the principal T-type channel in the substantia nigra, is downregulated in PD models and patient tissues. In a pretreatment paradigm, SAK3 restored Cav3.1 function, improving motor deficits, neuronal survival, and mitochondrial integrity. Metabolomic analysis revealed SAK3 drives metabolic shifts toward glycine/serine pathways and enriches mitochondrial oxidative phosphorylation genes. Mechanistically, SAK3 promotes calcium influx, activating the SphK1/S1P/Akt pathway to enhance mitochondrial function—stabilizing membrane potential, boosting oxidative phosphorylation, and rebalancing apoptosis regulators. Collectively, our study suggests that the effects of SAK3 are associated with Cav3.1 activationl and it orchestrates a protective response in preventive PD models by engaging the SphK1/S1P signaling axis, thereby stabilizing mitochondria and inhibiting apoptosis. These findings reveal a potential downstream effector pathway associated with Cav3.1 activation and position the SphK1/S1P network as a promising therapeutic target for further investigation in PD. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give... [797 chars]