The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder for which available treatments provide symptom relief but do not stop disease progression. Mitochondria, and in particular mitochondrial dynamics, have been postulated as plausible pharmacological targets. Mitochondria-targeted antioxidants have been developed to prevent mitochondrial oxidative damage, and to alter the involvement of reactive oxygen species (ROS) in signaling pathways. In this study, we have dissected the effect of MitoQ, which is produced by covalent attachment of ubiquinone to a triphenylphosphonium lipophilic cation by a ten carbon alkyl chain. MitoQ was tested in an in vitro PD model which involves addition of 6-hydroxydopamine (6-OHDA) to SH-SY5Y cell cultures. At sublethal concentrations of 50μM, 6-OHDA did not induce increases in protein carbonyl, mitochondrial lipid peroxidation or mitochondrial DNA damage. However, after 3h of treatment, 6-OHDA disrupts the mitochondrial morphology and activates the machinery of mitochondrial fission, but not fusion. Addition of 6-OHDA did not increase the levels of fission 1, mitofusins 1 and 2 or optic atrophy 1 proteins, but does lead to the translocation of dynamin related protein 1 from the cytosol to the mitochondria. Pre-treatment with MitoQ (50nM, 30min) results in the inhibition of the mitochondrial translocation of Drp1. Furthermore, MitoQ also inhibited the translocation of the pro-apoptotic protein Bax to the mitochondria. These findings provide mechanistic evidence for a role for redox events contributing to mitochondrial fission and suggest the potential of mitochondria-targeted therapeutics in diseases that involve mitochondrial fragmentation due to oxidative stress.

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

“…Although our findings indicate that increased mitochondrial ROS production is at least partly attributed to mitochondrial fragmentation, prior studies have demonstrated that extrinsic ROS can cause mitochondrial fragmentation (13,38,45). Furthermore, ROS within CSE has been proposed as the representative mechanism for toxicity (49).…”

“…chondrial fragmentation in the model of Parkinson's disease, an age-related neurodegenerative disorder (45). Hence, it is plausible that ROS in the CSE is responsible for modification of Drp1, resulting in activation and translocation to the mitochondria.…”

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

“…It is interesting that mitochondrial therapies have shown beneficial effects in different models of neurodegenerative pathologies, where mitochondrial dysfunction and apoptotic cell death are known to be involved, such as AD (Fossati, Ghiso & Rostagno, 2012b; Moreira, Carvalho, Zhu, Smith & Perry, 2010), Parkinson's disease (Solesio, Prime et al., 2013; Solesio, Saez‐Atienzar, Jordan & Galindo, 2012), and Huntington's disease (Solesio, Saez‐Atienzar, Jordan & Galindo, 2013). …”

Splitting up the powerhouse: structural insights into the mechanism of mitochondrial fission

“…ROS are initially formed by the premature release of electrons from the ETC and the reduction of molecular oxygen to form the superoxide radical Á O 2 -which can damage mitochondrial components including mtDNA, respiratory chain complexes and lipid membranes [66,67]. Increases in mitochondrial fragmentation and ROS have been observed in many disease states including diabetes, ischaemia reperfusion injury (IRI), AD and PD [68][69][70][71][72]. In IRI, the production of ROS in the reperfusion stage results in fragmentation of the mitochondrial network [73].…”