Mitochondrial metabolism in Parkinson's disease impairs quality control autophagy by hampering microtubule-dependent traffic

Abstract

Abnormal presence of autophagic vacuoles is evident in brains of patients with Parkinson's disease (PD), in contrast to the rare detection of autophagosomes in a normal brain. However, the actual cause and pathological significance of these observations remain unknown. Here, we demonstrate a role for mitochondrial metabolism in the regulation of the autophagy-lysosomal pathway in ex vivo and in vitro models of PD. We show that transferring mitochondria from PD patients into cells previously depleted of mitochondrial DNA is sufficient to reproduce the alterations in the autophagic system observed in PD patient brains. Although the initial steps of this pathway are not compromised, there is an increased accumulation of autophagosomes associated with a defective autophagic activity. We prove that this functional decline was originated from a deficient mobilization of autophagosomes from their site of formation toward lysosomes due to disruption in microtubule-dependent trafficking. This contributed directly to a decreased proteolytic flux of α-synuclein and other autophagic substrates. Our results lend strong support for a direct impact of mitochondria in autophagy as defective autophagic clearance ability secondary to impaired microtubule trafficking is driven by dysfunctional mitochondria. We uncover mitochondria and mitochondria-dependent intracellular traffic as main players in the regulation of autophagy in PD.

Autophagy and microtubules – new story, old players

“…In the context of neurodegenerative diseases, the link between MT-acting drugs and autophagy could also prove to be important. For example, in hybrid cells harbouring mitochondria from Parkinson's patients, mitochondria dysfunction alters the MT network and causes an accumulation of autophagosomes and an impaired clearance of both p62 and a-synuclein (Arduíno et al, 2012). Interestingly, in these cells, Taxol improves autophagic flux, most likely because it restores MT integrity.…”

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

“…Some of these defects are partially reversed by over-expression of parkin, pink1, DJ1, or the mitochondrial chaperone TRAP1 that requires phosphorylation by pink1 for functional activity (62, 349), suggesting a prominent role of autophagy in this process (445). Impaired autophagy due to mutations in parkin or pink1 impacts mitochondrial function by inhibiting mitophagy (257), and mitochondrial dysfunction directly inhibits autophagy by interfering with microtubule-dependent transport of autophagosomes, ultimately increasing intracellular levels of ROS and associated lysosomal leakage (17,112). Lysosomal deficiency and a-synuclein rich Lewy bodies reactive for the autophagosomal marker LC3 have been reported in the SN of PD brains and mouse models of PD, supporting this sequence of events (445).…”

Autophagic activity in neuronal cell death

“…Neurotoxins like rotenone and MPTP mimic PD pathology by inhibiting complex I of the mitochondrial electron transport chain and causing ROS generation [103][104][105] . Defective mitochondria may disrupt the Neurosci Bull June, 2015 6 microtubule-dependent trafficking of autophagosomes to lysosomes further, decreasing the clearance of aggregates and ROS even more [106] . These conditions also favor the mitochondrial release of cytochrome c into the cytosol, promoting cell death by apoptosis [107] .…”