Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy

Marta Zaninello, Konstantinos Palikaras, Deborah Naon, Keiko Iwata, Stephanie Herkenne, Ruben Quintana-Cabrera, Martina Semenzato, Francesca Grespi, Fred N. Ross-Cisneros, Valerio Carelli, Alfredo A. Sadun, Nektarios Tavernarakis and Luca Scorrano ()
Additional contact information
Marta Zaninello: Veneto Institute of Molecular Medicine
Konstantinos Palikaras: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Deborah Naon: Veneto Institute of Molecular Medicine
Keiko Iwata: Veneto Institute of Molecular Medicine
Stephanie Herkenne: Veneto Institute of Molecular Medicine
Ruben Quintana-Cabrera: Veneto Institute of Molecular Medicine
Martina Semenzato: Veneto Institute of Molecular Medicine
Francesca Grespi: University of Padova
Fred N. Ross-Cisneros: Doheny Eye Institute
Valerio Carelli: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital
Alfredo A. Sadun: Doheny Eye Institute
Nektarios Tavernarakis: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas
Luca Scorrano: Veneto Institute of Molecular Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract In autosomal dominant optic atrophy (ADOA), caused by mutations in the mitochondrial cristae biogenesis and fusion protein optic atrophy 1 (Opa1), retinal ganglion cell (RGC) dysfunction and visual loss occur by unknown mechanisms. Here, we show a role for autophagy in ADOA pathogenesis. In RGCs expressing mutated Opa1, active 5’ AMP-activated protein kinase (AMPK) and its autophagy effector ULK1 accumulate at axonal hillocks. This AMPK activation triggers localized hillock autophagosome accumulation and mitophagy, ultimately resulting in reduced axonal mitochondrial content that is restored by genetic inhibition of AMPK and autophagy. In C. elegans, deletion of AMPK or of key autophagy and mitophagy genes normalizes the axonal mitochondrial content that is reduced upon mitochondrial dysfunction. In conditional, RGC specific Opa1-deficient mice, depletion of the essential autophagy gene Atg7 normalizes the excess autophagy and corrects the visual defects caused by Opa1 ablation. Thus, our data identify AMPK and autophagy as targetable components of ADOA pathogenesis.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-17821-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17821-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-17821-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().