Mito ROS dysfunction leads to Proteostasis, impaired

Under oxidative stress, the proteostasis function becomes burdened with proteins modified by ROS (Powers et al., 2009; Zaltieri et al., 2015). These changed proteins can lead to further misfolding and aggregation of proteins (especially in non-dividing cells, like neurons). Particularly in DA cells, oxidative stress from dopamine metabolism and dopamine auto-oxidation may selectively increase their vulnerability to CI inhibitors (such as rotenone) and cause additional deregulation of protein degradation (Lotharius and Brundin, 2002; Esteves et al., 2011). As most oxidised proteins get degraded by UPS and ALP (McNaught and Jenner, 2001), mitochondrial dysfunction and subsequent deregulation of proteostasis play a pivotal role in the pathogenesis of PD (Sherer et al., 2002; Fornai et al., 2005; Pan et al., 2008; Dagda et al., 2013). It is also well documented that increased oxidative stress changes the protein degradation machinery and leads to a reduction of proteasome activity (Lin and Beal, 2006; Schapira, 2006).

Based on the existing in vitro and in vivo data it is suggested that mitochondrial dysfunction impairs protein homoeostasis through oxidative and nitrosative stress resulting in protein aggregation, damaged intracellular transport of proteins and cell organelles.

• Paraquat 0.5 mM decreases mitochondrial complex V activity, ATP production and proteasome activity in SH-SY5Y cells. All these effects increase in time (from 6 to 48 h) and are significant at 24 and 48 h of treatment. In addition, PQ signi!cantly decreases proteasome 19S subunit – but not 20S – only at 48 h. However, since this 19S subunit drops later than proteasome activity decrease, it could not have caused proteasome dysfunction. Signi!cant increased levels of a-syn and ubiquitinated proteins are also evident at 24 and 48 h following PQ exposure. SH-SY5Y death occurred only at 48 h. Cell death is dose dependent (PQ 0.05 – 1 mM) and is significant at 0.5 and 1 mM (57 and 75% respectively). PQ induces mitochondrial dysfunction and proteasome impairments leading to neuronal death (Yang and Tiffany-Castiglioni, 2007).
• Reduced mitochondrial membrane potential and proteasome inhibition has been also observed for 0.2 mM PQ as early as 3 h after exposure in SH-SY5Y cells. A slight but significant effect also occurs at 0.02 mM PQ at longer time (6 h). 0.2 mM PQ-induced effects precede neuronal death (12 h; no death observed at 0.02 mM). Transfection of the heat shock protein HDJ-1 (that attenuate protein aggregation without altering ROS production, as measured by DCF) in SH-SY5Y cells attenuates 0.2 mM PQ-induced mitochondrial membrane potential decrease at 6 h (from 50% to 80%). This suggests that protein aggregation also contribute to the loss of mitochondrial membrane potential (Ding and Keller, 2001).
• Paraquat (10 mg/kg, once a week for 3 weeks) in combination with DJ-1 de!ciency decreases ATP levels, proteasome activities, proteasome subunits levels and increases ubiquitinated proteins in the ventral midbrain including SNpc. None of these effects is observed at the striatum (Yang et al., 2007). DJ-1 has been suggested to contribute to mitochondrial integrity due to its localisation in the mitochondrial matrix and inter-membrane space (Zhang et al., 2005) and its antioxidant action (Taira et al., 2004). Likewise, exposure to PQ and deficiency of DJ-1 might cooperatively induce mitochondrial dysfunction resulting in ATP depletion and contribute to proteasome dysfunction in the brain.
• Paraquat (10 mg/kg i.p.) induced signi!cant increase in lipid peroxides (LPO) in ventral midbrain (VM), striatum (STR) and frontal cortex (FCtx), maximum in VM after 5 doses (2.4 times the control). An elevated LPO level was still present in VM after 28 days. Moreover, the activity of 20S proteasome in STR was altered (increased 40–50%) after a single dose and slightly reduced after 5 doses (Prasad et al., 2007). The temporal activation of proteasomal activity at 1 and 24 h after single dose was explained by the fact that carbonylated proteins moderately undergo degradation by UPS (Poppek and Grune, 2006). Sublethal proteasome inhibition induces neurons to increase proteasome activity and promotes resistance to oxidative injury (Lee et al., 2004).

• The exact molecular link from mitochondrial dysfunction to disturbed proteostasis is not known. It is not clear which is the oxidative modi!cation that drives the process.
• Proteostasis incidence is higher than mitochondrial dysfunction at PQ 0.5 mM (Yang and Tiffany-Castiglioni, 2007) but not at PQ 0.2 mM (Ding and Keller, 2001) at the same time point in SH-SY5Y cells. These results suggest that, in vitro, at doses higher than 0.2 mM PQ might involve mechanisms other than mitochondrial dysfunction.
• The sequence of events that link mitochondrial dysfunction to proteases inhibition is not entirely clear, proteosomal dysfunction might contribute to mitochondrial dysfunction (Ding and Keller, 2001). On the other side, sublethal proteasome inhibition induces neurons to increase pretoasome activity and promotes resistance to oxidative injury (Lee et al., 2004), whereas oxidative stress can increase proteasome activity early in the sequence leading to cell death in vitro (Holtz et al., 2006).
• A vicious circle is observed that make it dif!cult to establish an exact quantitative relationship between mitochondrial and proteosomal dysfunction. This task needs a better dose- and timerelated definition of PQ effect on those two events that is actually lacking.
• Lack of evidences of the link between mitochondrial dysfunction and disturbed proteostasis in WT animals exposed to PQ.
• Distinct unfolded protein response (UPR) signalling branches could have specific and even opposite consequences on neuronal survival depending on the disease input (Hetz and Mollereau, 2014). Proteostasis impairment at the level of the endoplasmic reticulum (ER) is emerging as a driving factor of dopaminergic neuron loss in PD. ER stress engages the activation of the UPR adaptive reaction to recover proteostasis or trigger apoptosis of damaged cells. PQ may induce ER stress (Huang et al., 2012).
• A genetic screening in yeast revealed that one of the major physical targets of a-Synuclein is Rab1, an essential component of the ER-to-Golgi trafficking machinery (Cooper et al., 2006; Gitler et al., 2008). Overexpression of Rab1 in animal models of PD reduced stress levels and protected dopaminergic neurons against degeneration (Coune et al., 2011).

ne: negative.

There are currently no known Feedforward/Feedback loops influencing this KER.