Open Access

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:

BIOCELL 2026, 50(10), 5 https://doi.org/10.32604/biocell.2026.081268

Received 27 February 2026; Accepted 07 May 2026; Issue published 22 September 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.

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Keywords

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