Fungal-Derived Decahydrofluorene Alkaloids Promote Mitochondrial Resilience and Neuroprotection in Cellular and Animal Models of Parkinson’s Disease

Parkinson’s disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 exhibited a favorable safety profile and protected SHSY5Y against 6-hydroxydopamine- (6-OHDA), rotenone-, and 1-Methyl-4-phenylpyridinium-iodide (MPP+)-induced neurotoxicity by preserving mitochondrial membrane potential and network integrity. Transcriptomic analyses revealed selective restoration of gene-expression programs associated with oxidative phosphorylation, mitochondrial bioenergetics, and stress adaptation disrupted by MPP+. CL0179 also enhanced SIRT1 activity under MPP+ stress, whereas pharmacological SIRT1 inhibition partially attenuated protection of mitochondrial membrane potential and cell viability. In LRRK2-G2019S astrocytes, CL0179 reduced ROS and α-synuclein accumulation and restored mitochondrial organization, while in human dopaminergic neurons, it attenuated toxin-induced mitochondrial depolarization and preserved neuronal architecture. To overcome the low production of CL0179, we generated the structurally related analogue CL0670. Both compounds crossed the blood–brain barrier and protected mouse primary cortical neurons, while CL0670 improved motor deficits in a 6-OHDA mouse model. Collectively, these compounds promote mitochondrial resilience and stress-adaptive neuroprotection, supporting their potential for PD and related neurodegenerative disorders.