MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1α

Abstract

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNc). Although mitochondrial dysfunction is the critical factor in the pathogenesis of PD, the underlying molecular mechanisms are not well understood, and as a result, effective medical interventions are lacking. Mitochondrial fission and fusion play important roles in the maintenance of mitochondrial function and cell viability. Here, we investigated the effects of MitoQ, a mitochondria-targeted antioxidant, in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo PD models. We observed that 6-OHDA enhanced mitochondrial fission by decreasing the expression of Mfn1, Mfn2 and OPA1 as well as by increasing the expression of Drp1 in the dopaminergic (DA) cell line SN4741. Notably, MitoQ treatment particularly upregulated the Mfn2 protein and mRNA levels and promoted mitochondrial fusion in the presence of 6-OHDA in a Mfn2-dependent manner. In addition, MitoQ also stabilized mitochondrial morphology and function in the presence of 6-OHDA, which further suppressed the formation of reactive oxygen species (ROS), as well as ameliorated mitochondrial fragmentation and cellular apoptosis. Moreover, the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was attributed to the upregulation of Mfn2 induced by MitoQ. Consistent with these findings, administration of MitoQ in 6-OHDA-treated mice significantly rescued the decrease of Mfn2 expression and the loss of DA neurons in the SNc. Taken together, our findings suggest that MitoQ protects DA neurons in a 6-OHDA induced PD model by activating PGC-1α to enhance Mfn2-dependent mitochondrial fusion.

Ferulic acid reinstates mitochondrial dynamics through PGC1α expression modulation in 6‐hydroxydopamine lesioned rats

“…We found that 6‐OHDA exposure reduced PGC1α mRNA expression and its protein expression in cytosol (Figures b and b). This is consistent with previous reports that observed that mitochondrial Complex I inhibitors such as 6‐OHDA reduced PGC1α expression (Xi et al, ). Our data also show that FA upregulates PGC1α mRNA and protein expression in lesioned animals, which is once again suggestive of the potential of FA to alleviate mitochondrial dysfunction.…”

Nitroxide Radical-Containing Redox Nanoparticles Protect Neuroblastoma SH-SY5Y Cells against 6-Hydroxydopamine Toxicity

“…Similar direction of changes was seen when the intensity of mitochondrial staining with MitoTracker Red was compared ( Figure 2). This phenomenon might be correlated with the fact that several studies have shown that 6-OHDA affects mitochondrial fusion and fission causing an imbalance in mitochondrial dynamics, and it is proven that it may contribute to the pathogenesis of neurodegenerative diseases [61][62][63]. Previous studies demonstrated that 6-OHDA (albeit at a high concentration of 150 μM) caused a loss of cell viability and mitochondrial depolarization [55,64].…”

Acrolein Aggravates Secondary Brain Injury After Intracerebral Hemorrhage Through Drp1-Mediated Mitochondrial Oxidative Damage in Mice

“…The mitochondrial membrane potential (MMP) was measured using tetramethyl rhodamine ethyl ester (TMRE) staining, and mitochondrial reactive oxygen species (ROS) production using MitoSox Deep Red staining, as previously described [33]. Primary neurons were incubated with 10 nmol/L TMRE (T669, Life Technologies, Carlsbad, CA) or 5 nmol/L MitoSox (M36008, Invitrogen, Carlsbad, CA) for 0.5 h. Then, the cells were washed 3 times with Hanks' Balanced Salt Solution to remove the medium.…”