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

Abstract

Why mitochondria progressively fail in aging neurons remains a fundamental question in neurobiology. Although bioenergetic decline and oxidative stress are hallmarks of aging, whether redox signaling remodels mitochondrial nucleoids (mt-nucleoids) to impair neuronal bioenergetics remains unclear. Using aged mouse neurons and human induced pluripotent stem cell (iPSC)-derived neurons, we demonstrate that redox-driven mt-nucleoid remodeling underlies reduced mtDNA transcript abundance and bioenergetic decline. Combining minimal photon fluxes (MINFLUX) nanoscopy with single-molecule transcription mapping, we identify distinct mt-nucleoid architectures governed by mitochondrial transcription factor A (TFAM)-mediated mtDNA compaction. Aging-associated oxidative stress drives mt-nucleoid remodeling from compact, transcriptionally active structures toward decompacted forms with reduced mtDNA transcript abundance and impaired mitochondrial ATP production. This remodeling involves species-specific TFAM redox mechanisms: cysteine oxidation promotes human TFAM polymerization, whereas methionine oxidation weakens mouse TFAM-mtDNA interactions. Notably, expressing an oxidation-resistant TFAM variant restores mt-nucleoid organization, mtDNA transcript abundance, and ATP production in aged neurons, identifying mt-nucleoid architecture as a potential target for preserving neuronal bioenergetics during aging.