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REVIEW

The Metabolic-Epigenetic Crosstalk: Mitochondrial Retrograde Signaling in Telomere Homeostasis

Michele Manganelli*
Department of Precision and Regenerative Medicine and Ionian Area, University of Bari-Aldo Moro, Bari, Italy
* Corresponding Author: Michele Manganelli. Email: email

BIOCELL https://doi.org/10.32604/biocell.2026.081268

Received 27 February 2026; Accepted 07 May 2026; Published online 21 May 2026

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+/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+ 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.

Keywords

Mitochondria; nucleus; human telomerase reverse transcriptase; succinate dehydrogenase (SDH); Acetyl-CoA; sirtuins; epigenetics; senescence; genomic instability

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