Neuroglial transmitophagy and Parkinson's disease

Abstract

Mitophagy is essential for the health of dopaminergic neurons because mitochondrial damage is a keystone of Parkinson's disease. The aim of the present work was to study the degradation of mitochondria in the degenerating dopaminergic synapse. Adult Sprague–Dawley rats and YFP‐Mito‐DAn mice with fluorescent mitochondria in dopaminergic neurons were injected in the lateral ventricles with 6‐hydroxydopamine, a toxic that inhibits the mitochondrial chain of dopaminergic neurons and blockades the axonal transport. Dopaminergic terminals closest to the lateral ventricle showed an axonal fragmentation and an accumulation of damaged mitochondria in 2–9 μ saccular structures (spheroids). Damaged mitochondria accumulated in spheroids initiated (showing high Pink1, parkin, ubiquitin, p‐S65‐Ubi, AMBRA1, and BCL2L13 immunoreactivity and developing autophagosomes) but did not complete (mitochondria were not polyubiquitinated, autophagosomes had no STX17, and no lysosomes were found in spheroids) the mitophagy process. Then, spheroids were penetrated by astrocytic processes and DAergic mitochondria were transferred to astrocytes where they were polyubiquitinated (UbiK63+) and linked to mature autophagosomes (STX17+) which became autophagolysosomes (Lamp1/Lamp2 which co‐localized with LC3). Present data provide evidence that the mitophagy of degenerating dopaminergic terminals starts in the dopaminergic spheroids and finishes in the surrounding astrocytes (spheroid‐mediated transmitophagy). The neuron‐astrocyte transmitophagy could be critical for preventing the release of damaged mitochondria to the extracellular medium and the neuro‐inflammatory activity which characterizes Parkinson's disease.

Extracellular Mitochondria Signals in CNS Disorders

“…In this study, electron microscopy and confocal microscopy determined that retinal ganglion cells transferred mitochondriacontained vesicles to retinal astrocytes to eliminate damaged mitochondria through so called transmitophagy. In the context of PD, the mechanism of transmitophagy may be crucial to maintain mitochondrial function in dopaminergic neurons and prevent neuroinflammation mediated by disrupted mitochondrial secretion (Morales et al, 2020). In this study, Morales and colleagues observed that damaged dopaminergic neurons via 6-OHDA infusion generated spheroid-like structure containing mitochondria and transferred them to adjacent astrocytes for digesting damaged mitochondria through STX17/Lamp1/Lamp2/LC3+ autophagolysosomes FIGURE 1 | Intercellular mitochondrial transfer.…”

“…Extracellular mitochondria and mtDNA may provide a glimpse into the status of tissue metabolism, disease severity and recovery in the CNS. (Morales et al, 2020). Collectively, the transmitophagy may be a mechanism of mitochondrial quality control through intercellular mitochondrial transfer in the CNS.…”

Neuron-Astrocyte Interactions in Parkinson’s Disease

“…As mentioned above, astrocytes engulf the aggregated α-synuclein and damaged mitochondria released from neuronal cells and degrade neuronal waste via the proteasome and autophagy (mitophagy) pathways [94,95,234]. Thus, phagocytic activity of astrocytes is important for neuroprotection ( Figure 2).…”

“…The uptake of extracellular α-synuclein occurs via endocytosis in neurons and glial cells [91]. In particular, microglia and astrocytes are able to clean extracellular α-synuclein aggregates via internalization and degradation [92][93][94]. Recently, astrocytes were reported to engulf and degrade α-synuclein aggregates via proteasome and autophagy pathways [95], suggesting that astrocytes exert dopaminergic neuroprotection by clearing excess extracellular toxic α-synuclein.…”

“…Recently, it was reported that damaged mitochondria are internalized and degraded by surrounding astrocytes [99]. Morales et al [94] demonstrated that the damaged mitochondria of degenerating dopaminergic terminals were transferred to striatal astrocytes for their degradation. The authors also reported that striatal astrocytes engulf dopaminergic debris, which contains TH, DAT, and α-synuclein [100].…”