Alterations in energy metabolism and glucose uptake are associated with the physiopathology of several NDs including PD
[7,8,56][6][7][42]. Glucose is the main source of energy in the brain and the regulation of its metabolism is critical for brain physiology
[50][41]. This is consistent with the observation that
DJ-1β mutants show a dysregulation of carbohydrates metabolism (
Figure 42). Supporting this, a decrease in glucose levels in the iPSC-derived DA neurons mutant for
PARK2 was previously observed
[72][53]. In fact, glucose is the sole substrate that can supply the rapid energy demand of neuronal cells through glycolysis
[56,73][42][54]. Therefore, an increase in glucose consumption through this pathway to restore ATP levels could explain its reduction in our PD model flies
[7,74][6][55]. Glycolysis is an ATP-producing pathway that could provide considerable amounts of ATP in a less efficient manner than oxidative phosphorylation to support the acute energy demands in neurons
[73,75][54][56]. DJ-1 was described as participating in the activity of complex I of ETC binding and stabilizing it
[14][13]. Accordingly, TCA cycle reduction and a higher NADH/NAD
+ ratio in the PD model flies suggest the existence of an alteration of this complex and mitochondrial dysfunction, which was also observed in a MPTP-induced PD cell model
[76][57]. Thus, our results show that a shift from TCA cycle to glycolysis is produced in PD model flies
[7,41,77][6][58][59]. In addition, it was reported that a reduction in Aco activity caused neurotoxicity in mesencephalic rat cultures, due to the loss of its activity as ROS and an iron biosensor
[52,78][60][61]. Moreover,
Aco mutant flies exhibited a reduced locomotor activity, shortened lifespan, and increased cell death in the developing brain, as well as glycolysis and TCA cycle disturbances that led to decreased ATP levels
[52][60]. Some of the phenotypes are similar to those observed in
DJ-1β mutant flies
[7,27][6][26]. On the other hand, the reduction in SDH activity leads to the activation of the mammalian target of rapamycin (mTOR) and the sterol regulatory element binding protein (SREBP), which contribute to lipid accumulation in neurons, as observed in several NDs, and produce excitotoxicity, thus participating in PD pathogenesis and development
[79,80][62][63]. In addition, the finding of reduced malate levels in PD model flies is also noteworthy. Malate is an intermediate of the TCA cycle that is metabolized from fumarate by the fumarate hydratase enzyme. Interestingly, it was shown that the expression of fumarate hydratase was reduced in the DA neurons of the SNpc in the brains of iPD patients
[81][64]. Thus, our results and these observations suggest that a decrease in the activity of both enzymes might be relevant to PD pathogenesis.
Figure 2. Alterations in carbohydrate content in DJ-1β mutant flies. Relative NMR signals of selected carbohydrates in between (a) 1-day-old DJ-1β mutant and control flies, (b) 15-day-old DJ-1β mutant and control flies, and (c) 1-day-old and 15-day-old DJ-1β mutant flies. Relative NADH/NAD+ ratio in (d) 1-day-old DJ-1β mutant and control flies, (e) 15-day-old DJ-1β mutant and control flies, and (f) 1-day-old and 15-day-old DJ-1β mutant flies. Relative NMR signals of TCA cycle intermediates comparing (g) 1-day-old DJ-1β mutant and control flies, (h) 15-day-old DJ-1β mutant and control flies, and (i) 1-day-old and 15-day-old DJ-1β mutant flies. In all cases, error bars show s.d. from twelve independent samples (*, p < 0.05; **, p < 0.01; ***, p < 0.001).
Although TCA cycle activity is decreased in
DJ-1β mutant flies, there is an increase in some pathway intermediates such as fumarate (
Figure 42g,h). TCA cycle metabolites can be produced by other pathways, as could be happening with fumarate and the UC
[55][65]. UC is responsible for the excretion of the nitrogen that cannot be used in amino acid metabolism, and is related to the TCA cycle by fumarate, which is transported into the mitochondria, where it can be used as a substrate of TCA cycle
[55,56][65][42]. The enhanced expression of
arg and
Argl in PD model flies could lead to a general increase in UC activity and to higher fumarate levels, as observed in the metabolomic analyses (
Figure 42g,h). Supporting these results, an increase in ArgL activity was observed in a zebrafish PD model based on
DJ-1 deficiency
[82][66]. Changes in
arg expression levels were also reported to have implications in the brain, although its role in this tissue is not yet known
[83][67]. In addition, an enhancement of UC could serve to remove the excess of ammonia caused by the increased amino acid catabolism observed in
DJ-1β mutant flies, as previously reported in Alzheimer’s disease
[83][67].