Fig. 10: Inhibition of CPT1 counteracts rotenone-induced pathological mechanisms by targeting both extra- and intracerebral systems.

Rotenone or PARK2 knockout results in blockade of mitochondrial complex I and upregulation of CPT1 and thereby β-oxidation. The upregulation of CPT1(A) is attenuated by the pharmacological antagonist etomoxir and the hypomorphic CPT1A allele (P479L mutation). Upregulation of CPT1 results in extracerebral effects such as the production of reactive oxidative species, production of pro-inflammatory cytokines, disruption of mitochondrial homeostasis and dysbiosis in the gut. Furthermore, this upregulation exacerbates intracerebral pathological mechanisms such as neuroinflammation, oxidative stress, aggregation of α-synuclein oligomers, mitochondrial dysfunction, which results in dopamine loss due to the death of dopaminergic neurons. Inhibition of CPT1(A) causes a shift toward glucose metabolism, causing amelioration of these disease mechanisms.