Redox-dependent remodeling of mitochondrial nucleoids contributes to bioenergetic decline during neuronal aging.

Redox-driven remodeling of mitochondrial nucleoids in aged mouse neurons shifts mt-nucleoid architecture from compact, transcriptionally active to decompacted, reducing mtDNA transcript abundance and ATP production.

• Why it matters: Mitochondrial failure in aging neurons is linked to oxidative stress, but how redox signaling remodels mt-nucleoids to impair neuronal bioenergetics was unclear.
• What they did: Using aged mouse neurons and human iPSC-derived neurons, the study combined MINFLUX nanoscopy with single-molecule transcription mapping to relate TFAM-mediated mtDNA compaction to distinct mt-nucleoid architectures.
• The result: Oxidative stress drove decompaction and lower mtDNA transcripts with impaired mitochondrial ATP production, and expressing an oxidation-resistant TFAM variant restored mt-nucleoid organization, transcript abundance, and ATP in aged neurons.

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