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.

This work was supported by supported by the National Natural Science Foundation of China (No. U23A20423, 82371265), Joint Funds for the innovation of Science and Technolog, Fujian province (No.2025Y9380, No.2025Y9351), Fujian Provincial Natural ScienceFoundation of China (No.2026J001643) Foundation for Cultivated Young Talents of Fujian Province, China (No.2025YC002) and Sponsored by Fujian provincial health technology project (No. 2025QNA019). These authors contributed equally: Lina Chen, Jiaqia Ke, Yingqing Wang.

Department of Neurology, Center for Cognitive Neurology, Institute of Clinical Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China Lina Chen, Jiaqia Ke, Yingqing Wang, Zhiting Chen, Haoling Xu, En Huang, Guoen Cai, Yuqi Zeng & Qinyong Ye Clinical Research Center for Precision Diagnosis and Treatment of Neurological Diseases of Fujian Province, Fuzhou, 350001, China Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, 350001, China Correspondence to Guoen Cai, Yuqi Zeng or Qinyong Ye. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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