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Prophylactic nicotinamide treatment protects from rotenone-induced neurodegeneration by increasing mitochondrial content and volume
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Department of Ophthalmology, University of Iceland, Reykjavik, Iceland.ORCID iD: 0000-0003-0218-4563
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
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2024 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 37Article in journal (Refereed) Published
Abstract [en]

Leber’s hereditary optic neuropathy (LHON) is driven by mtDNA mutations affecting Complex I presenting as progressive retinal ganglion cell dysfunction usually in the absence of extra-ophthalmic symptoms. There are no long-term neuroprotective agents for LHON. Oral nicotinamide provides a robust neuroprotective effect against mitochondrial and metabolic dysfunction in other retinal injuries. We explored the potential for nicotinamide to protect mitochondria in LHON by modelling the disease in mice through intravitreal injection of the Complex I inhibitor rotenone. Using MitoV mice expressing a mitochondrial-tagged YFP in retinal ganglion cells we assessed mitochondrial morphology through super-resolution imaging and digital reconstruction. Rotenone induced Complex I inhibition resulted in retinal ganglion cell wide mitochondrial loss and fragmentation. This was prevented by oral nicotinamide treatment. Mitochondrial ultrastructure was quantified by transition electron microscopy, demonstrating a loss of cristae density following rotenone injection, which was also prevented by nicotinamide treatment. These results demonstrate that nicotinamide protects mitochondria during Complex I dysfunction. Nicotinamide has the potential to be a useful treatment strategy for LHON to limit retinal ganglion cell degeneration.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024. Vol. 12, no 1, article id 37
Keywords [en]
Mitochondria, Neurodegeneration, Nicotinamide, Optic nerve, Retina, Retina ganglion cells
National Category
Neurosciences Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-222236DOI: 10.1186/s40478-024-01724-zISI: 1176539900001PubMedID: 38429841Scopus ID: 2-s2.0-85186470382OAI: oai:DiVA.org:umu-222236DiVA, id: diva2:1845261
Funder
Swedish Research Council, 2022–00799Karolinska InstituteStiftelsen Kronprinsessan Margaretas arbetsnämnd för synskadadeAvailable from: 2024-03-18 Created: 2024-03-18 Last updated: 2024-03-18Bibliographically approved

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Jóhannesson, Gauti

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