Dysregulated iron metabolism in C. elegans catp-6/ATP13A2 mutant impairs mitochondrial function

Mutations in the human ATP13A2 gene are associated with an early-onset form of Parkinson's disease (PD) known as Kufor Rakeb Syndrome (KRS). Patients with KRS show increased iron deposition in the basal ganglia, suggesting iron toxicity-induced neurodegeneration as a potential pathogenesis asso...

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Bibliographic Details
Published in:Neurobiology of disease 2020-06, Vol.139, p.104786-104786, Article 104786
Main Authors: Anand, Nikhita, Holcom, Angelina, Broussalian, Michael, Schmidt, Minna, Chinta, Shankar J., Lithgow, Gordon J., Andersen, Julie K., Chamoli, Manish
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - metabolism
Animals
ATP13A2
Autophagy
C. elegans
Caenorhabditis elegans
Caenorhabditis elegans Proteins - metabolism
Catp-6
Dopaminergic Neurons - metabolism
Humans
Iron - metabolism
Iron chelation
Lysosomes
Lysosomes - metabolism
Mitochondria - metabolism
Mitochondrial function
Mutation
Parkinson Disease - metabolism
Parkinson's disease
Parkinsonian Disorders - metabolism
Proton-Translocating ATPases - metabolism
TFEB
Urolithin A
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Summary:Mutations in the human ATP13A2 gene are associated with an early-onset form of Parkinson's disease (PD) known as Kufor Rakeb Syndrome (KRS). Patients with KRS show increased iron deposition in the basal ganglia, suggesting iron toxicity-induced neurodegeneration as a potential pathogenesis associated with the ATP13A2 mutation. Previously we demonstrated that functional losses of ATP13A2 disrupt the lysosomes ability to store excess iron, leading to reduce survival of dopaminergic neuronal cells. To understand the possible mechanisms involved, we studied a Caenorhabditis elegans mutant defective in catp-6 function, an ortholog of human ATP13A2 gene. Here we show that catp-6 mutant worms have defective autophagy and lysosomal function, demonstrate characteristic PD phenotypes including reduced motor function and dysregulated iron metabolism. Additionally, these mutants have defective mitochondrial health, which is rescuable via iron chelation or mitophagy induction. •Loss in C. elegans catp-6 disrupts autophagy and lysosmal function•CATP-6 mediates iron homesotais and mitochondrial function•Iron chelation and mitophagy as potential therapeutic approach to resuce mitochondrial defects in catp-6/ATP13A2 mutants
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2020.104786