Nrf2 activation attenuates the early suppression of mitochondrial respiration due to the α-synuclein overexpression

Abstract

Backgroundα-synuclein (SNCA) accumulation in the substantia nigra is one of the characteristic pathologies of Parkinson's disease (PD). A53T missense mutations in the SNCA gene has been proved to enhance the expression of SNCA and accelerate the onset of PD. Mitochondrial dysfunction in SNCA aggregation has been under debate for decades but the causal relationship remains uncertain. At a later stage of PD, the cellular dysfunctions are complicated and multiple factors are tangled. Our aim here is to investigate the mitochondrial functional changes and clarify the main causal mechanism at earlier-stage of PD.MethodsWe used the mutant A53T SNCA-expressed neuro 2a (N2a) cells without detectable cell death to investigate: 1) whether SNCA overexpression impairs the mitochondrial respiration and biogenesis. 2) The role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signal in SNCA–induced mitochondria dysfunction.ResultsAccompanying with the increment of SNCA, reactive oxygen species (ROS) accumulation was increased. The maximal respiratory capacity was suppressed. Meanwhile, mitochondrial complex 1 activity and the activity of nicotinamide adenine dinucleotide (NADH) cytochrome C reductase (NCCR) were decreased. Moreover, the mitochondrial DNA (mtDNA) copy number was decreased. On the other hand, the nuclear peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), Nrf2, and the cytosolic mitochondrial transcription factor A (TFAM) were increased at an early stage and declined thereafter. Above factors triggered by SNCA were reversed by tBHQ, a Nrf2 activator.ConclusionThese results suggested that at an early stage, SNCA-overexpressed increase mtROS accumulation, mitochondrial dysfunction and mtDNA decrement. Nrf2, PGC-1α and TFAM were upregulated to compromise mitochondrial dysfunction. tBHQ effectively reversed the SNCA-induced mitochondrial dysfunction.

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

“…The elevated levels of ROS as a consequence of α‐Syn expression may originate from increase ROS produced within mitochondria (Fu et al . ). Addressing the increase in ROS levels caused by α‐Syn via antioxidants such as Selenomethionine (Kumar et al .…”

“…Indeed the cellular overexpression of a-Syn increases ROS and sensitizes cells to the various oxidative stressor, lowering the threshold of such insult required to induce apoptosis (Junn and Mouradian 2002). The elevated levels of ROS as a consequence of a-Syn expression may originate from increase ROS produced within mitochondria (Fu et al 2018). Addressing the increase in ROS levels caused by a-Syn via antioxidants such as Selenomethionine (Kumar et al 2005) and Curcumin (Wang et al 2010) proved an effective means of reducing a-Syn toxicity.…”

“…Addressing the increase in ROS levels caused by a-Syn via antioxidants such as Selenomethionine (Kumar et al 2005) and Curcumin (Wang et al 2010) proved an effective means of reducing a-Syn toxicity. Both tert-Butylhydroquinone a pharmacological activation of the antioxidant transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and coenzyme Q10, which acts as exogenous electron carrier during mitochondria biogenesis can effectively reduce excess ROS produced by mitochondria in pathological conditions and restore mitochondria function (Fu et al 2018). Interestingly, the co-overexpression of DJ-1 may exert some of its protected properties against a-Syn toxicity via diminishing oxidative stress (Zhou and Freed 2005).…”

Potential Applications of NRF2 Inhibitors in Cancer Therapy

“…The vast majority of them encode for metabolic enzymes that readily detoxify electrophiles (i.e., phase I/II/III drug metabolism) or scavenge ROS molecules (i.e., antioxidant systems) [60, 61], in order to restore the intracellular redox homeostasis and minimize the oxidative damage [60, 62]. However, increasing evidence indicates that NRF2 can also regulate other biological processes with physiopathological relevance in human diseases (e.g., tumors) such as proliferation [62–67], differentiation [68–72], inflammation [73–76], autophagy [77–81], apoptosis [66, 82–85], mitochondrial function or biogenesis [86–92], and several metabolic pathways involved in iron/heme [32, 93–97], glucose [98–101], glutamine [101–103], lipid [104–107], NADPH [108–110], and pentose phosphate metabolism [111–114]. In the following sections, we will discuss the oncogenic alterations in the NRF2/KEAP1 pathway that confer a selective advantage to malignant cells and their relevance as therapeutic targets in the treatment of cancer.…”

Tainted air: The link between pollution and Alzheimer's disease

“…Here, Fu et al. [29] examine the relationship between mitochondrial dysfunction and the accumulation of α-synuclein (SNCA) into Lewy bodies, the pathological hallmark of Parkinson's disease. Using a SNCA mutant that is prone to aggregation, they find that the accumulation of SNCA is accompanied by an increase in reactive oxygen species and decrease in both mitochondrial fitness and mitochondrial DNA copy number.…”