@Article{biocell.2026.081268,
AUTHOR = {Michele Manganelli},
TITLE = {The Metabolic-Epigenetic Crosstalk: Mitochondrial Retrograde Signaling in Telomere Homeostasis},
JOURNAL = {BIOCELL},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/biocell/online/detail/26932},
ISSN = {1667-5746},
ABSTRACT = {Telomere homeostasis is intrinsically integrated into the cellular metabolic network through a complex mito-nuclear communication system. Telomeric chromatin acts as a sensitive sensor of mitochondrial flux, where the stability of telomeres depends on mitochondrial-derived metabolites essential for epigenetic remodeling. Three primary axes govern this control: (1) Acetyl-CoA-mediated histone acetylation necessary for human Telomerase Reverse Transcriptase (hTERT) expression; (2) the competitive balance between α-ketoglutarate/succinate, modulating Jumonji-C (JmjC)-demethylases and Ten-eleven translocation (TET) enzymes; (3) the mitochondrial NAD<sup>+</sup>/NADH ratio, governing sirtuin 6 (SIRT6) fidelity. The bidirectional non-coding RNA shuttling, TERC-53 fragment, acts as a retrograde signal of mitochondrial distress. A shift in these metabolic ratios—often induced by succinate dehydrogenase (SDH) deficiency or NAD<sup>+</sup> depletion—leads to epigenetic hardening, characterized by telomeric hypermethylation and repressive chromatin state. Sustained metabolic failure triggers the extranuclear translocation of hTERT, generating a mitohormetic trade-off that prioritizes mitochondrial repair over nuclear replicative capacity. This review aims to provide a comprehensive overview of the functional pathways through which mitochondrial dysfunctions act as a primary driver of genomic instability, providing a comprehensive roadmap to restore epigenetic integrity and cellular homeostasis in age-related pathologies.},
DOI = {10.32604/biocell.2026.081268}
}