Universität zu Köln

Zaninello, Marta, Palikaras, Konstantinos, Sotiriou, Aggeliki, Tavernarakis, Nektarios ORCID: 0000-0002-5253-1466 and Scorrano, Luca ORCID: 0000-0002-8515-8928 (2022). Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy. Cell Death Differ., 29 (1). S. 167 - 178. LONDON: SPRINGERNATURE. ISSN 1476-5403

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Abstract

Mitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+ levels, and decreased axonal mitochondrial density. Chelation of Ca2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Zaninello, Marta UNSPECIFIED UNSPECIFIED UNSPECIFIED Palikaras, Konstantinos UNSPECIFIED UNSPECIFIED UNSPECIFIED Sotiriou, Aggeliki UNSPECIFIED UNSPECIFIED UNSPECIFIED Tavernarakis, Nektarios UNSPECIFIED orcid.org/0000-0002-5253-1466 UNSPECIFIED Scorrano, Luca UNSPECIFIED orcid.org/0000-0002-8515-8928 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-595141
DOI:	10.1038/s41418-021-00847-3
Journal or Publication Title:	Cell Death Differ.
Volume:	29
Number:	1
Page Range:	S. 167 - 178
Date:	2022
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	1476-5403
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RETINAL GANGLION-CELLS; MITOCHONDRIAL DYSFUNCTION; OPA1 DEFICIENCY; QUALITY-CONTROL; ENERGY SENSOR; CALCINEURIN; AUTOPHAGY; AMPK; DEGRADATION; HOMEOSTASIS Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59514