Nexus between mitochondrial function, iron, copper and glutathione in Parkinson's disease

Abstract

Parkinson's disease is neuropathologically characterised by loss of catecholamine neurons in vulnerable brain regions including substantia nigra pars compacta and locus coeruleus. This review discusses how the susceptibility of these regions is defined by their shared biochemical characteristics that differentiate them from other neurons. Parkinson's disease is biochemically characterised by mitochondrial dysfunction, accumulation of iron, diminished copper content and depleted glutathione levels in these regions. This review also discusses this neuropathology, and provides evidence for how these pathological features are mechanistically linked to each other. This leads to the conclusion that disruption of mitochondrial function, or iron, copper or glutathione metabolism in isolation provokes the pathological impairment of them all. This creates a vicious cycle that drives pathology leading to mitochondrial failure and neuronal cell death in vulnerable brain regions.

Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain

“…A more stable pool of metals may be represented by plasma bound organelles such as mitochondria, which internalise Fe, Cu, Mn and Zn for both specific biological function or the synthesis of metalloproteins such as Fe-sulfur complexes or cytochrome c oxidase. Although mitochondrial dysfunction, and resulting effects on metal levels, are proposed to contribute to neuronal death in Parkinson’s disease, 32 the fractionation technique used here may have masked subtle changes in mitochondrial metal levels and specific isolation of mitochondria from other membrane-encapsulated metals in Parkinson’s disease and control samples would be required.…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…The neuropathological features of PD are the loss of catecholamine neurons in vulnerable brain regions, including substantia nigra (SN) pars compacta (SNc) and blue spot, and the PD is biochemically characterized by mitochondrial dysfunction, accumulation of iron, diminished copper content, and depleted GSH levels in these regions (Liddell and White, 2018). It was beneficial for PD when using ferroptosis inhibitor-iron chelator deferiprone for PD treatment in a randomized controlled trial (Devos et al, 2014), and deferiprone could protect SN neurons and prevent PD progression in this trial.…”

“…So it is concluded that ferroptosis may play an important role in the progression of PD disease, and that PD has been undergoing clinical evaluation through a conservative chelation mode based on drug-mediated iron redistribution (Moreau et al, 2018), and it might be a chance to cure PD in the future. Mitochondrial damage occurs in the early stages of PD and a large body of evidence indicates that the activity of mitochondrial complex | was impaired in tissues after the death of PD, and another typical feature of PD was that GSH is selectively depleted from the (Liddell and White, 2018). These characteristics are the most typical characteristics of ferroptosis, suggesting that ferroptosis may play a key role in the progression of PD disease.…”

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

“…Copper's general role in redox and oxidative stress is pertinent to SCN clock function and neurodegeneration. A proportional balance of Cu and reduced glutathione/GSH are important for decreasing oxidative damage and increasing cell survival, particularly in response to neurotoxic conditions (Du et al., ; Hatori, Clasen, Hasan, Barry, & Lutsenko, ; Kumar, Kalita, Bora, & Misra, ; Liddell & White, ; Mercer et al., ; Samuele et al., ; White & Cappai, ; White et al., ). Mitochondrial energetics plays a critical role in determining cellular Cu distribution and metabolism along with ROS and GSH levels; highly metabolically active neurons must coordinate antioxidant processes to protect against ROS/oxidative stress (Grimm & Eckert, ; Requejo‐Aguilar & Bolanos, ; Stefanatos & Sanz, ).…”

“…Finally, there is evidence that Cu can modulate transcription in mammalian (Kamiya, Takeuchi, Fukudome, Hara, & Adachi, ; Yan et al., ) and nonmammalian cells (Park et al., ; Sameach et al., ), either directly or indirectly. For example, Cu can modulate phosphodiesterases and phosphatases, as well as several transcription factors (SP1, AP1, NRF2) (Chen et al., ; Jiang et al., ; Liddell & White, ; Mattie et al., ). Notably, some of these pathways and potential interacting, elements (e.g., JNK, GSK3, FoxO signaling) play a role in circadian rhythms, highlighting a need to investigate their interaction with Cu in the SCN (Asher & Schibler, ; Barthel, Ostrakhovitch, Walter, Kampkotter, & Klotz, ; Besing et al., ; Hamann, Petroll, Grimm, Hartwig, & Klotz, ; Kon, Sugiyama, Yoshitane, Kameshita, & Fukada, ; Mattie et al., ; Paul et al., ; Sun et al., ; Wu et al., ; Yoshitane et al., ; Zheng et al., ).…”