Loss of mitofusin 2 links beta‐amyloid‐mediated mitochondrial fragmentation and Cdk5‐induced oxidative stress in neuron cells

Abstract

Mitochondrial dysfunction is implicated in age-related degenerative disorders such as Alzheimer's disease (AD). Maintenance of mitochondrial dynamics is essential for regulating mitochondrial function. Ab oligomers (AbOs), the typical cause of AD, lead to mitochondrial dysfunction and neuronal loss. AbOs have been shown to induce mitochondrial fragmentation, and their inhibition suppresses mitochondrial dysfunction and neuronal cell death. Oxidative stress is one of the earliest hallmarks of AD. Cyclin-dependent kinase 5 (Cdk5) may cause oxidative stress by disrupting the antioxidant system, including Prx2. Cdk5 is also regarded as a modulator of mitochondrial fission; however, a precise mechanistic link between Cdk5 and mitochondrial dynamics is lacking. We estimated mitochondrial morphology and alterations in mitochondrial morphologyrelated proteins in Neuro-2a (N2a) cells stably expressing the Swedish mutation of amyloid precursor protein (APP), which is known to increase AbO production. We demonstrated that mitochondrial fragmentation by AbOs accompanies reduced mitofusin 1 and 2 (Mfn1/2) levels. Interestingly, the Cdk5 pathway, including phosphorylation of the Prx2-related oxidative stress, has been shown to regulate Mfn1 and Mfn2 levels. Furthermore, Mfn2, but not Mfn1, over-expression significantly inhibits the AbO-mediated cell death pathway. Therefore, these results indicate that AbO-mediated oxidative stress triggers mitochondrial fragmentation via decreased Mfn2 expression by activating Cdk5-induced Prx2 phosphorylation.

The Role of Cdk5 in Alzheimer’s Disease

“…Moreover, an inhibition of Cdk5 activity can save mitochondrial damage and prevent neuronal cell death upstream of mitochondrial dysfunction [128]. Cdk5 may cause oxidative stress by disrupting the antioxidant system such as Prx2 and further trigger mitochondrial fragmentation [125]. Moreover, it is reported that the balance of mitochondrial dynamics is sensitive to oxidative stress [129].…”

“…A lot of studies have proved that oxidative stress and mitochondrial dysfunction occur in an early stage of AD pathology, which precedes the formation of detectable plaques and tangles [125]. Cdk5 is as a direct participation in oxidative stress and mitochondrial abnormality in neurons as well as the generation of Aβ and glutamate, two key players in AD pathology (Fig.…”

Mitochondrial fission and fusion in secondary brain damage after CNS insults

“…4 Deletion and/or inhibition of Mfn1 and Mfn2 results in failure of fusion leading to formation of very small mitochondrial fragments with reduced mass, and decreased transport of mitochondrial component proteins leading to neurodegeneration. 19,[70][71][72][73] Deletion of Mfn1 leads to no change in phenotype up to one year of age, whereas deletion of Mfn2 in a subset of dopaminergic neurons leads to hunched and hypoactive mice by 5 weeks of age. 73 Furthermore, loss of Mfn2 results in mitochondrial fragmentation and severe age-dependent motor deficits that precede the loss of dopaminergic terminals in the striatum.…”

Astragaloside IV rescues MPP+-induced mitochondrial dysfunction through upregulation of methionine sulfoxide reductase A

“…AS-IV also prevented MPP + -induced mitochondrial fragmentation via MsrA, while knocking down MsrA attenuated this protective effect. This effect may be attributed to the fact that MsrA protects mitofusin from oxidation and maintains normal mitochondrial function (43). Since mitochondria are the primary source of ROS and are a major target of oxidative damage, mitochondrial protein dysfunction likely increases MPP + -induced oxidative damage.…”