Prophylactic nicotinamide treatment protects from rotenone-induced neurodegeneration by increasing mitochondrial content and volume.

Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE

Original Publication: London : BioMed Central, [2013]-

Rotenone*/toxicity ; Rotenone*/metabolism ; Optic Atrophy, Hereditary, Leber*/genetics ; Optic Atrophy, Hereditary, Leber*/metabolism ; Optic Atrophy, Hereditary, Leber*/therapy; Mice ; Animals ; Niacinamide/adverse effects ; Niacinamide/metabolism ; Mitochondria/metabolism ; Retinal Ganglion Cells ; Electron Transport Complex I/metabolism

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.
(© 2024. The Author(s).)

Comment in: Acta Neuropathol Commun. 2024 Apr 5;12(1):53. doi: 10.1186/s40478-024-01768-1. (PMID: 38581047)

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2018-02124 Vetenskapsrådet; 2022-00799 Vetenskapsrådet

Keywords: Mitochondria; Neurodegeneration; Nicotinamide; Optic nerve; Retina; Retina ganglion cells

03L9OT429T (Rotenone)
25X51I8RD4 (Niacinamide)
EC 7.1.1.2 (Electron Transport Complex I)

Date Created: 20240301 Date Completed: 20240304 Latest Revision: 20240624

20240624

PMC10908050

10.1186/s40478-024-01724-z

38429841