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Home/ Journals/ BIOCELL/ Vol.50, No.10, 2026/ 10.32604/biocell.2026.081268

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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 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.

Keywords

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

1 Introduction

The maintenance of telomeric integrity has historically been framed within the context of the mitochondrial free radical theory of aging (MFRTA) [1,2], where mitochondria are the primary sources of reactive oxygen species (ROS) that induce direct DNA damage and genome attrition [3,4,5]. However, emerging evidence is shifting this paradigm toward a more complex mito-nuclear communication network, known as mitochondrial-nuclear signaling [6,7,8].

This communication involves two distinct pathways: anterograde signaling, through which the nucleus regulates mitochondrial biogenesis, and retrograde signaling, a surveillance pathway by which mitochondria communicate their functional status to the nucleus to trigger compensatory responses [9]. Retrograde signaling is activated under conditions of mitochondrial stress and operates through several conserved mechanisms, including the Mitochondrial Unfolded Protein Response (UPRmt) and the Integrated Stress Response (ISR) [10,11]. These pathways rely on a diverse array of signaling molecules, such as ROS, mitochondrial DNA (mtDNA) fragments, the AMP-activated protein kinase (AMPK) as an energy sensor, and key intermediates of the Tricarboxylic Acid (TCA) cycle [12]. While retrograde signaling influences multiple cellular processes, its role in epigenetic regulation represents a sophisticated layer of genome control [13].

Mitochondria represent dynamic metabolic hubs that actively influence the nuclear epigenetic landscape [14,15,16]. At the heart of this metabolic-epigenetic wiring lies the observation that epigenetic modifiers—including histone acetyltransferases (HATs) and DNA methyltransferases (DNMTs), function not as autonomous effectors, but as metabolic sensors [17,18,19]. HATs add an acetyl group to histone tails (H3K9, H3K27, H3K56, H4K16), which neutralizes their positive charge and weakens their interaction with negatively charged DNA. Acetylation acts as a molecular opener, promoting a relaxed, transcriptionally active euchromatin state [20]. Methylation and demethylation involve the addition or removal of methyl groups to DNA or histones (H3K9, H3K4). Unlike acetylation, the effect of methylation is context-dependent: while it can facilitate gene silencing through compact heterochromatin formation, it is also important to maintain structural boundaries within the genome. Demethylation, conversely, serves to reset these marks, allowing for dynamic plasticity [21]. The cell reads its energetic status through the availability of mitochondrial metabolites to decide which genes to turn on or off. Their catalytic activity is strictly dependent upon the availability of specific mitochondrial-derived substrates and co-factors, particularly Acetyl-CoA, α-ketoglutarate (α-KG), and NAD+ [22,23]. Consequently, fluctuations in mitochondrial Tricarboxylic Acid (TCA) cycle act as a metabolic signal that ripples beyond bioenergetics, extending their influence into alterations of the epigenetic code [24,25,26].

Telomeric chromatin is particularly sensitive to metabolic fluctuations (Fig. 1) [27,28]. Indeed, the sensitivity of telomeres to mitochondrial fluctuations is not universal, but rather a tunable function of the cell differentiation status and specific bioenergetic demands. In pluripotent and adult stem cells, where mitochondrial metabolism is often primed toward glycolysis and telomere reverse transcriptase (hTERT) constitutive activation, the metabolic-nuclear flux serves as a permissive signal for self-renewal [25,29]. Conversely, in highly oxidative differentiated cells, the gradual decline in mitochondrial efficiency acts as a signal for telomere regulation and replicative senescence [30,31,32]. This is particularly evidenced when the mitochondrial-nuclear metabolite flux is disrupted—as occurs in succinate dehydrogenase (SDH) deficiency or NAD+ depletion—as the cell undergoes a metabolic-epigenetic imbalance. This uncoupling leads to the loss of the protective chromatin architecture, leaving the telomere vulnerable to premature shortening and instability [33,34,35]. It becomes clear that telomere homeostasis is a function of mitochondrial health.

This review aims to address the functional pathways through which mitochondrial metabolites govern telomeric stability, highlighting that mitochondrial dysfunction is a primary driver of genomic instability through the disruption of the metabolic-epigenetic signaling axis, providing a comprehensive roadmap to restore epigenetic integrity and cellular homeostasis in age-related pathologies.

images

Figure 1: Mitochondrion-nucleus feedback loop. The picture illustrates the crosstalk between cellular metabolism and the structural integrity of nuclear DNA. Within the mitochondrion, the TCA cycle generates key metabolites such as citrate and α-KG. Once transported into the cytosol, citrate is converted into Acetyl-CoA by the enzyme ACLY, providing acetyl groups (Ac) for histone acetylation, while α-KG acts as an essential cofactor for demethylation (Me) modifications, directly influencing the epigenetics of telomeric DNA. In parallel, the NAD+ pool regulates the activity of crucial nuclear enzymes: SIRT6, which promotes telomere deacetylation and stability, and PARPs, involved in DNA damage repair. The Shelterin complex interacts with circadian clock proteins to protect the TTAGGG telomeric repeat sequences. A retrograde signal is represented by TERC-53, a non-coding RNA fragment that bridges mitochondrial distress to nuclear response. The disruption of this homeostatic balance compromises genomic stability and accelerates cellular decline. Abbreviations: TCA, Tricarboxylic Acid; α-KG, α-Ketoglutarate; ACLY, ATP Citrate Lyase; Acetyl-CoA, Acetyl Coenzyme A; Ac, Acetylation; Me, Methylation; NAD+, Nicotinamide Adenine Dinucleotide; SIRT6, Sirtuin 6; PARPs, Poly(ADP-ribose) Polymerases; TERC-53, Telomerase RNA Component 53-nt fragment; TRF1/2, Telomeric Repeat-binding Factor 1/2; TIN2, TRF1-interacting Nuclear Protein 2; RAP1, Repressor/Activator Protein 1; POT1, Protection of Telomeres 1; TPP1, TIN2-interacting Protein 1; BMAL1, Brain and Muscle ARNT-Like 1; CLOCK, Circadian Locomotor Output Cycles Kaput. This figure was created with BioRender.com.

2 Molecular Landscape of the Mito-Nuclear Communication

The metabolic-epigenetic crosstalk is a complex regulatory network where mitochondria act as environmental sensors for the nucleus. This communication relies on a diverse set of intermediates, including TCA cycle metabolites, non-coding RNAs, and transiently translocating proteins that function as molecular messengers. Table 1 provides a comprehensive overview of these actors, their associated metabolites, and their specific roles in maintaining telomeric homeostasis.

Table 1: Molecular mediators of the Mitochondrial-Telomere retrograde signaling axis.

AbbreviationFull NameAssociated MetaboliteFunctional Role in Telomere HomeostasisReferences
ACLYATP Citrate LyaseAcetyl-CoAConverts mitochondrial citrate into Acetyl-CoA, fueling histone acetylation (H3K9ac, H3K27ac) at the hTERT promoter to maintain its expression. [36,37,38]
AMPKAMP-activated Protein KinaseATP/AMP ratioMaster energy sensor; triggers mitochondrial retrograde signaling and activates PGC-1α to promote TERRA expression under metabolic stress.[30,39,40]
ATRXAlpha-Thalassemia/X-linkedN/AChromatin remodeler that maintains telomeric heterochromatin; its loss is a hallmark of the Alternative Lengthening of Telomeres (ALT) pathway.[41,42,43]
EZH2/SUZ12PRC2 Complex subunitsSAMMethyltransferases that interact with TERRA to deposit repressive H3K27me3 marks using SAM as a methyl donor, ensuring telomeric silencing.[44,45]
hTERTTelomerase Reverse TranscriptaseN/AUnder oxidative stress, it translocates to mitochondria to protect mtDNA and respiratory function.[46,47,48]
ISR/UPRmtIntegrated Stress ResponseMito-stress signalsSignaling cascades that communicate mitochondrial proteotoxic stress to the nucleus to modulate cellular lifespan and adaptation.[10,11]
JHDMsJmjC-domain Demethylasesα-KG/Succinateα-KG-dependent enzymes that remove repressive marks (H3K9me3) to maintain telomere plasticity. Competitively inhibited by succinate.[49,50,51]
NAMPTNicotinamide phosphoribosyl-transferaseNAD+Rate-limiting enzyme in NAD+ metabolism; links the circadian clock to SIRT6-mediated telomere protection.[52,53]
NRF1Nuclear Respiratory Factor 1N/ATranscription factor that coordinates mitochondrial biogenesis and promotes TERRA transcription during physiological stress.[54,55]
SDHSuccinate DehydrogenaseSuccinateComplex II enzyme; its deficiency causes succinate accumulation, leading to epigenetic hardening and telomeric instability.[34,35,56]
SIRT6Sirtuin 6NAD+NAD+-dependent deacetylase; ensures T-loop stability and prevents R-loop formation.[57,58]
TERC-53Telomerase RNA Component (fragment 53)Mito-stress signalsA cytoplasmic fragment of TERC that shuttles to the nucleus as a retrograde signal of mitochondrial distress, bypassing canonical telomerase roles.[59]
TERRATelomeric Repeat RNAN/ALong non-coding RNA acts as a scaffold for chromatin modifiers (PRC2 and LSD1) and interacts with TERC-53 for mito-nuclear signaling.[44,60]

Note: N/A: not applicable.

The complexity of this communication lies in its hierarchical decision-making logic. As illustrated in Fig. 2, the cell translates mitochondrial functional states (energetic, oncometabolite, and redox status) into specific nuclear fates. This stepwise transduction ensures that telomere stability is dynamically tuned to the bioenergetic capacity of the cell, transitioning from a permissive state of self-renewal under optimal conditions to epigenetic hardening and senescence when mitochondrial distress signals predominate.

images

Figure 2: Stepwise functional roadmap of mitochondrial-telomere retrograde signaling. The picture illustrates the causal hierarchy of the mito-nuclear crosstalk, moving from metabolic inputs to genomic outcomes. (Top) Mitochondrial Input: Normal oxidative phosphorylation (OXPHOS) (left) maintains high levels of nicotinamide adenine dinucleotide (NAD+), α-ketoglutarate (α-KG), and Acetyl-CoA, whereas Mitochondrial Distress (right) leads to NAD+ depletion, succinate accumulation, and telomerase RNA component fragment 53 (TERC-53) release. (Middle) Transduction: These metabolic states are sensed by epigenetic modifiers. In homeostatic conditions, sirtuin 6 (SIRT6) and histone acetyltransferases (HATs) ensure telomere capping and an open chromatin state. Conversely, mitochondrial distress triggers the inhibition of histone demethylases (JHDMs) and SIRT6, alongside GAPDH sequestration by TERC-53. (Bottom) Nuclear Outcome: The signaling axis dictates the cellular fate, leading to genomic stability and self-renewal (left) or the epigenetic hardening (H3K9me3), base excision repair (BER) failure, and cellular senescence (right). This figure was created with BioRender.com.

3 The Energetic Axis: Acetyl-CoA and Telomeric Chromatin Accessibility

3.1 Acetyl-CoA Production and Compartmentalization

Acetyl-CoA is the key metabolic intermediate produced by the catabolism of carbohydrates, lipids, and amino acids [61]. The acetyl group is transported out of the mitochondria through an indirect shuttle system: acetyl-CoA inside the mitochondrion condenses with oxaloacetate to form citrate. Citrate passes into the cytoplasm across the inner mitochondrial membrane through the Citrate carrier (SLC25A1) [62]. In the cytosol, citrate is cleaved by citrate lyase (ACLY) to regenerate acetyl-CoA [36]. The cytosolic pool of citrate is also sustained by the reductive carboxylation of α-KG mediated by IDH1. Under conditions of mitochondrial impairment or metabolic shift, IDH1 reverses the canonical flux to generate isocitrate and subsequently citrate, which ACLY then cleaves into Acetyl-CoA [63].

Seminal evidence highlighted that ACLY can translocate into the nucleus, providing a compartmentalized nuclear pool of Acetyl-CoA for histone acetylation [64,65]. Accordingly, ACLY nuclear translocation in fibroblasts upon fibrotic stimulation, facilitating TGF-β-mediated myofibroblast activation by promoting H3K27ac at fibrotic gene loci [37]. On the other hand, in cisplatin-resistant hepatocellular carcinoma cells, the stabilization of nuclear ACLY by NAT10-mediated acetylation at K468 prevents its degradation through SQSTM1-mediated proteasomal pathways. This enhances the nuclear acetyl-CoA levels, increasing H3K27ac at chemoresistance-related genes like CYP2C9 and PIK3R1 [38,66].

Interestingly, in most somatic cells, the hTERT promoter (the on/off switch for telomerase) is typically embedded in a nuclease-resistant, closed chromatin structure that silences gene expression. However, an adequate bioenergetic supply facilitates a switch to an accessible euchromatin state, characterized by markers such as H3K9ac, H3K27ac, and H3K4me2/3, allowing key transcription factors like c-Myc and Sp1 to initiate transcription [67,68]. c-Myc binds to specific E-box sequences (5′-CACGTG-3′) within the hTERT promoter [69]. The convergence of c-Myc/Sp1 serves as a metabolic sensor by recruiting HATs, such as TRRAP and p300/CBP [70,71]. TRRAP is essential for this selectivity, as it bridges nuclear ACLY activity directly to the c-Myc cluster. This process acts as a metabolic sensor: during G1-S phases, the nucleus requires enormous amounts of acetyl-CoA for histone acetylation. While ACLY maintains a basal level of acetylation, translocation of the pyruvate dehydrogenase complex (PDC) produces acetyl-CoA directly from pyruvate within the nucleus, providing a high-flux, spatiotemporal boost of acetyl-CoA directly to chromatin during the high-stress window of DNA replication [64,72,73].

3.2 Metabolic Sensing and hTERT Promoter Regulation

This spatial substrate channeling ensures that Acetyl-CoA is utilized in situ to catalyze the acetylation of surrounding histones, effectively opening the hTERT chromatin while other genomic regions remain unaffected [74]. This is particularly evident in the context of hTERT promoter mutations [75]. Cytosine-to-thymine (C > T) transitions at positions -124 bp (C228T), and -146 bp (C250T) are the most frequent genetic alterations within the hTERT promoter in medulloblastomas [76], hepatocellular carcinomas (HCC) [77], urothelial carcinomas of the bladder [78], melanomas [79], and primary glioblastomas (GBM) [80]. These mutations result in the generation of de novo binding sites (consensus sequence 5′-CCGGAA-3′) for the ETS family of transcription factors [81]. Specifically, the transcription factor GABPA selectively recognizes and binds to the mutated promoter, whereas it shows no affinity for the wild-type sequence [82]. This specific binding recruits the transcriptional machinery, leading to the overexpression of hTERT and subsequently promoting cellular immortalization. Therefore, the oncogenic potential of hTERT mutations is functionally dependent on the bioenergetic state [83,84].

3.3 TERRA Modulation and the Bioenergetic Checkpoint

Consistently, in mammalian cells, the Telomeric Repeat-containing RNA (TERRA) transcript is essential for cis/trans telomere capping to protect the T-loop architecture [44,85,86]. TERRA interacts with H3K9me3 and HP1 (heterochromatin protein 1) proteins [87], the histone methyltransferase SUV39H1 [88], and with chromatin remodeling complexes such as NoRC (nucleolar remodeling complex) [89], MORF4L2 (a component of the NuA histone acetyltransferase complex), and ARID1A [90]. NuA4 is responsible for the acetylation of histone H4 (H4Ac). This specific modification neutralizes the positive charge of the histone tails, reducing DNA torsional tension and favouring chromatin to open. Thus, RTEL1 helicases could remove G-quadruplexes and allow DNA polymerase to complete its work [91,92]. Without this dual-input of Acetyl-CoA, the TERRA-bound MORF4L2 cannot maintain the requisite chromatin flexibility of the subtelomeric region during S-phase [93].

Evidence suggests that telomere length (TL) itself can modulate metabolic signaling, establishing a retrograde feedback loop [94]. The telomere acts as a physical sensor that feedback-regulates the cell’s enzymatic capacity to maintain its own length through the Telomere Position Effect over Long Distance (TPE-OLD) or the non-telomeric binding of TRF2 to the hTERT promoter [95,96,97]. In cases of severe bioenergetic failure, the lack of substrates for the epigenetic machinery triggers a cascade of genomic instability [57,98]. The loss of histone acetylation results in replication fork stalling and the formation of DNA secondary G-quadruplexes [99,100]. These unresolved stalls result in persistent double-strand breaks (DSBs) at telomeric repeats [101]. In this context, the cell is forced to utilize the existing DSBs as substrates for homology-directed repair (HDR), effectively bypassing the need for telomerase through aberrant template switching [102,103,104]. Consequently, the Acetyl-CoA flux serves as a fundamental checkpoint: when the fuel for acetylation is exhausted, the cell is propelled toward senescence or aberrant genomic survival strategies.

4 The Control Axis: α-KG/Succinate and Telomeric Stability

4.1 Competitive Inhibition of 2-OGDD Enzymes by Succinate

Beyond acetylation, the mitochondrial-nuclear axis exerts a second layer of epigenetic control through the α-ketoglutarate (α-KG)/succinate ratio [49]. α-KG, produced in the mitochondrial matrix by isocitrate dehydrogenase (IDH), is the obligatory co-substrate for the 2-oxoglutarate-dependent dioxygenase (2-OGDD) superfamily [50]. This family includes TET (Ten-Eleven Translocation) DNA demethylases, which convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), and JmjC-domain-containing histone demethylases (JHDMs), such as KDM4B/C, which remove repressive marks like H3K9me3 and H3K27me3 [105,106,107]. An accumulation of succinate acts as a potent competitive inhibitor of 2-OGDDs. Specifically, succinate competes with α-KG for binding to the highly conserved Fe2+-containing active site of TET and JmjC enzymes, thereby blocking their catalytic activity [108].

Mitochondrial α-KG is exported to the cytosol through the oxoglutarate carrier SLC25A11 (OGC) in exchange for malate. On the other hand, mitochondrial succinate is exported to the cytosol through the dicarboxylate carrier SLC25A10. Once in the cytosol, their availability in the nucleus directly depends on the cytosolic α-KG/succinate ratio [62]. The α-KG/succinate ratio thus dictates the global methylome: a high ratio (high α-KG) promotes a permissive, hypomethylated state, whereas a low ratio (high succinate) triggers a hypermethylator phenotype. This low-ratio state, often termed CpG Island Methylator Phenotype (CIMP), leads to the hypermethylation of DNA and histones across the genome [109].

At telomeric and subtelomeric regions, this axis is critical for structural plasticity, although through distinct substrates. While subtelomeric regions are regulated by DNA methylation at CpG islands, the telomeric core—which lacks CpG sites—relies exclusively on histone marks [110,111]. TET and JmjC enzymes utilize α-KG to maintain these regions in a metabolically responsive state, facilitating the dynamic turnover of shelterin proteins and fine-tuning the transcription of TERRA [44,86,112,113].

4.2 SDH Deficiency and the Epigenetic Lock

Consistently, TERRA transcripts associate with the histone methyl transferase Polycomb Repressive Complex 2 (PRC2), through a direct interaction with the PRC2 components EZH2 and SUZ12 [44]. Furthermore, TERRA G-quadruplex acts as a scaffold for other telomere-binding proteins, such as the translocated in liposarcoma/fused in sarcoma protein (TLS/FUS) and TRF2 [114,115]. These interactions through the activity of Suv4-20h2, which associates with TLS/FUS, can promote H4K20me3 modification at telomeres [116]. Without this RNA scaffold, the telomere loses its ability to manage and organize its own heterochromatin, leading to structural fragility.

While a systemic lack of S-adenosylmethionine (SAM) could potentially leave methyltransferases catalytically starved, the pathological accumulation of succinate exerts a dominant inhibitory effect on the 2-OGDD family. This disruption shifts the telomeric landscape from a dynamic state to one of epigenetic inertia, leading to replication fork stalling and instability [104]. Mitochondrial compromises, such as loss-of-function mutations in succinate dehydrogenase (SDH), cause a massive accumulation of succinate, leading to an epigenetic silencing of the 2-OGDD family [117]. This process occurs not through mere energy depletion, but through the induction of a state of biochemical pseudohypoxia [118]. The pathological accumulation of succinate, acting as an oncometabolite, inhibits prolyl hydroxylases (PHDs) in the cytosol, leading to the constitutive stabilization of Hypoxia-Inducible Factor 1-alpha (HIF1α) even under normoxic conditions [117,119,120,121]. This stabilization triggers a profound biological paradox that explains the genomic instability observed in SDH-deficient tumors and chronic metabolic diseases. On one hand, stabilized HIF1α translocates to the nucleus and directly binds to the hTERT promoter, attempting to upregulate telomerase expression as an evolutionary rescue mechanism to counteract mitochondrial-induced cellular stress [122,123]. On the other hand, the succinate surplus that stabilizes HIF1α simultaneously functions as a competitive inhibitor of the TET and JmjC enzymes required to maintain telomeric chromatin accessibility [45]. Consequently, the cell faces a metabolic-epigenetic mismatch: it attempts to activate hTERT within a genomic environment that is physically inaccessible. This is driven by subtelomeric DNA hypermethylation and, crucially, by the persistence of H3K9me3 at the telomeric core due to JHDM inhibition [124,125,126]. This epigenetic lock prevents the functional translation of the HIF1α signal into effective telomere repair. Instead, the compromised binding of the shelterin complex to hypermethylated repeats—coupled with the inability of telomerase to access the T-loop—accelerates telomere attrition and favors aberrant DNA template switching [125,127], triggering a transition toward aberrant survival pathways such as the alternative lengthening of telomeres (ALT) pathway [128,129,130]. Moreover, this transition is significantly favored by the loss of ATRX, a chromatin remodeler frequently mutated in SDH-deficient tumors [41,42]. This epigenetic instability promotes the formation of extra-chromosomal telomeric circles (C-circles) and facilitates homology-directed repair (HDR), providing the genetic and metabolic ground for ALT [43,131].

4.3 Mitochondrial Cofactors: Pyrimidine Synthesis and FAD-Dependent Demethylation

Furthermore, the failure of the SDH-CoQ axis disrupts the de novo synthesis of pyrimidines via dihydroorotate dehydrogenase (DHODH), creating a localized depletion of dNTPs that further cripples any residual telomerase-mediated repair [132,133,134].

Complementary to the α-KG-dependent family, telomeric heterochromatin is further fine-tuned by Lysine-specific demethylase 1 (LSD1). Unlike JmjC enzymes, LSD1 does not require α-KG, but is strictly dependent on Flavin Adenine Dinucleotide (FAD) as a catalytic cofactor [61]. LSD1 orchestrates the oxidative demethylation of mono- and di-methylated H3K4 and H3K9, a process that reduces FAD to FADH2. Consequently, in case of ETC compromise, a decline in the mitochondrial FAD/FADH2 ratio limits LSD1 enzymatic turnover [135]. This metabolic bottleneck leads to the aberrant persistence of H3K4 methylation marks, which effectively opens the telomeric chromatin, facilitating the pathological transcription of TERRA and predisposing the locus to the formation of DNA-damaging R-loops [136,137].

5 The Surveillance Axis: NAD+ Bioavailability and SIRT6 Fidelity

5.1 SIRT6 as a Metabolic Sensor of NAD+

The NAD+/SIRT6 axis constitutes the third critical pillar of mitochondrial-nuclear communication. Nicotinamide adenine dinucleotide (NAD+) is the central redox cofactor for the mitochondrial electron transport chain (ETC), facilitating the transfer of electrons to generate the proton gradient necessary for ATP synthesis [138]. Functional mitochondria maintain a high NAD+/NADH ratio, which is essential for maintaining the catalytic activity of NAD+-dependent enzymes [52]. While acetyl-CoA and α-KG provide the building blocks and signals for chromatin remodeling, NAD+ serves as a real-time sensor of bioenergetic integrity that activates nuclear surveillance enzymes. These include the so-called longevity sirtuin, SIRT6 deacetylase, often referred to as the guardian of telomere stability [139,140].

The biochemical fidelity of SIRT6 is strictly governed by NAD+ bioavailability [58,141]. Unlike other sirtuins, SIRT6 possesses a low Kd (~27 μM) and high Km (~270–800 μM) for NAD+, making SIRT6 a true metabolic sensor due to its catalytic activity sensitive to fluctuations in the nuclear NAD+ pool and capable of adapting gene expression and DNA repair based on energy availability [142].

5.2 T-Loop Stability and TERRA Repression

Unlike other members of the sirtuin family, SIRT6 is constitutively tethered to chromatin and is indispensable for telomere stability [58]. Under metabolic homeostasis, mitochondrial Complex I maintains the NAD+/NADH balance, fueling SIRT6 to orchestrate telomeric protection through three primary NAD+-coordinated mechanisms. SIRT6 mediates H3K9 and H3K56 deacetylation to promote a stable heterochromatic structure. This specific deacetylation is a prerequisite for stabilizing the protective T-loop architecture, preventing the formation of aberrant telomeric DNA circles (t-circles) and suppressing illegitimate recombination [143,144]. Moreover, SIRT6 acts as a molecular scaffold for the recruitment of the shelterin complex TRF2 and the coordination of DNA repair machinery. It facilitates the recruitment of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ensuring that DBSs at telomeric ends are addressed by non-homologous end joining (NHEJ) [145,146,147]. Finally, in somatic contexts, SIRT6 prevents uncontrolled cellular proliferation and transcriptional leakage of TERRA, thereby protecting telomeres from inappropriate DNA damage response (DDR) activation [148,149]. Mechanistically, the H3K9 residue can be either acetylated or methylated, but never both simultaneously. When SIRT6 is active, it removes the acetyl group (H3K9Ac → H3K9). Thus, SUV39H1 can deposit the methylation mark (H3K9 → H3K9me3). Finally, HP1 binds to the H3K9me3 signal. In this state, TERRA transcription is maintained at basal, physiological levels. Without SIRT6, lysine 9 remains engaged by the acetyl group (H3K9Ac). Consequently, SUV39H1 is unable to act, H3K9me3 fails to form, HP1 is not recruited, and the telomere fails to compact. As a result, RNA polymerase II produces an excessive amount of TERRA. These transcripts then form R-loops (three-stranded DNA: RNA hybrids) on the telomeric DNA. During the S-phase, these structures block the replication fork, leading to double-strand breaks (DSBs) and the subsequent activation of the DDR [150,151].

5.3 The Bioenergetic-Telomeric Trap and PARP-1 Competition

When mitochondrial bioenergetics fail, the resulting reduction in NAD+ bioavailability compromises SIRT6 fidelity. Without sufficient NAD+, SIRT6 can no longer function as an epigenetic brake, leading to the deregulation of metabolic genes through the p53-mediated repression of PGC-1α and PGC-1β [152]. Consequently, the impaired HAT activity due to the localized Acetyl-CoA depletion may lead to reduced histone acetylation, potentially contributing to a transition toward a repressive, closed chromatin state. Without α-KG, TET/JmjC demethylases become blocked (hypermethylation). This bioenergetic-telomeric trap propels the cell toward a point of no return where replicative senescence becomes the inevitable outcome of systemic metabolic exhaustion [57,153]. This vulnerability is exacerbated by the competition for the same NAD+ pool with Poly(ADP-ribose) polymerase 1 (PARP-1) [154]. Activated by DNA damage—often a byproduct of mitochondrial ROS—PARP-1 acts as a metabolic sink, depleting nuclear NAD+ levels due to its higher affinity for the substrate [155]. This creates a lethal vicious cycle: the accumulation of telomeric damage recruits PARP-1, which further starves SIRT6 of NAD+, thereby accelerating telomeric uncapping and preventing efficient DNA repair [156,157].

6 The Extranuclear Translocation of hTERT: Translational Perspectives

6.1 Stress-Induced Nucleocytoplasmic Shuttling of hTERT

Beyond its canonical role within the nucleus, the catalytic subunit hTERT possesses a nucleocytoplasmic shuttling characteristic [46].

In homeostatic conditions, hTERT is predominantly nuclear. However, in response to oxidative stress (i.e., H2O2 exposure), hTERT is transiently exported to the cytosol. This process is mediated by the CRM1 (Exportin 1) pathway and the Ran-GTPase system [47,158]. hTERT possesses an evolutionarily conserved Nuclear Export Signal (NES) located within its C-terminus reverse transcriptase domain (residues 701–900). This signal is conditionally accessible: under basal conditions, the NES is sequestered within the protein tertiary structure. Upon oxidative stress, phosphorylation at specific residues (Tyr707) by Src-kinase or Abl-tyrosine-kinase induces a conformational change that exposes the NES for CRM1 recognition. This mechanism ensures that hTERT export is not a random process but a tightly regulated rescue strategy to protect hTERT from nuclear degradation and to prevent telomerase-induced de novo addition at fragile genomic sites during stress [159].

6.2 Mitochondrial TERT (mtTERT) and the Mitohormetic Trade-Off

Once in the cytosol, hTERT could also be directed to the mitochondria through a specific 20-amino acid amphipathic alpha-helix Mitochondrial Targeting Sequence (MTS), located at the N-terminus (residues 1–20) [160]. Here, it functions as a mitochondrial chaperone (mtTERT) through several integrated mechanisms. While initial studies focused on mtTERT binding to the ND1 and ND2 regions, more extensive mapping has revealed that mtTERT interacts with a broad array of mitochondrial loci, including 12S and 16S rRNA, ND4, ND5, COX I, COX III, and ATP synthase subunits 6 and 8, enhancing its resistance to oxidative damage and reducing the local production of ROS [161]. A compelling hypothesis proposes that mtTERT actively participates in mtDNA replication by utilizing mitochondrial tRNAs as primers. By favoring alternative origins of replication (mt-tRNA genes), mtTERT may limit the traditional strand displacement mode, which is notoriously prone to deletions [162]. Furthermore, mtTERT interacts with the RNA component of mitochondrial RNA processing (RMRP) and improves the activity of the electron transport chain (ETC), particularly Complex I, stabilizing membrane potential and ATP production [163,164]. Finally, mtTERT acts as a protein scaffold for mitochondrial transcripts, stabilizing mitochondrial ribosome function and ensuring efficient translation of respiratory proteins [165].

This movement represents a strategic metabolic pivot where hTERT transitions from a genomic enzyme to a mitochondrial protector. This mitohormetic strategy creates a functional trade-off designed to prioritize immediate cellular survival and bioenergetic maintenance at the direct expense of long-term replicative capacity [48,166]. The pharmacological modulation of this axis offers a promising therapeutic frontier. Molecules capable of stabilizing nuclear hTERT or, conversely, promoting its mitochondrial translocation could be used to fine-tune the balance between genomic stability and metabolic efficiency [167].

6.3 TERC-53 and the Retrograde Signaling of Mitochondrial Distress

The regulatory hierarchy between the nucleus and mitochondria is not a one-way round. The mitochondrial compartment is capable of incorporating and processing non-coding RNAs [168]. The telomerase RNA component (TERC) facilitates this bidirectional feedback loop. TERC-53 is a 53-nucleotide fragment derived from the 5′-end of TERC, and its cytosolic accumulation is dynamically regulated by mitochondrial function [59]. Under conditions of mitochondrial distress, TERC-53 accumulates in the cytosol, acting as a molecular decoy that traps glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the cytosol, thus preventing its translocation to the nucleus [59]. Nuclear GAPDH is essential for the stabilization and catalytic efficiency of Uracil-DNA Glycosylase (UNG), the primary enzyme responsible for removing pro-mutagenic uracil residues from DNA for the Base Excision Repair (BER) machinery. The resulting failure of the BER pathway leads to the accumulation of single-strand breaks [169]. This finding adds a critical layer to the metabolic axes previously discussed: the mitochondrial-telomere crosstalk is not only mediated by protein translocation (hTERT) or metabolite flux (Acetyl-CoA, NAD+), but also by non-coding RNA signals (TERC-53) that dictate the transition toward replicative arrest [59,169,170,171].

7 Spatiotemporal Regulation and Circadian Clock

The entire system is not static, but it follows a biological circadian rhythm. Telomere maintenance is finally dynamically synchronized within the circadian clock. It regulates the rhythmic availability of NAD+ through the rate-limiting enzyme NAMPT (Nicotinamide phosphoribosyltransferase). NAMPT expression is directly governed by the CLOCK: BMAL1 heterodimer, creating a 24-h oscillation in nuclear NAD+ levels. This temporal fluctuation implies that the surveillance capacity of SIRT6—and consequently the stability of the telomeric T-loop—is subject to a circadian window of vulnerability [53]. However, it should be mentioned that current literature regarding the direct circadian control of telomere-mitochondria crosstalk remains extremely limited. This knowledge gap is due to the significant methodological challenges in chronobiology research.

Finally, under Caloric Restriction (CR), a physiological state of low nutrient intake without malnutrition that shifts cellular priority toward survival and repair, the activation of the AMPK/PGC-1α pathway recruits Nuclear Respiratory Factor 1 (NRF1) to subtelomeric promoters, directly promoting TERRA expression, to ensure that the chromatin environment remains responsive [55,172].

8 Conclusion

In conclusion, the telomere acts as a metabolic antenna, sensing the state of the mitochondria to decide the cell fate. The transition towards cellular aging is not only a matter of physical DNA wear, but an epigenetic hardening due to the failure of mitochondrial signaling. Deciphering the language of this communication is essential for the generation of therapies in age-related pathologies. Consistently, age-related pathologies would require a holistic approach that views genomic stability as a direct reflection of mitochondrial health.

Acknowledgement: Not applicable.

Funding Statement: The author received no specific funding for this study.

Availability of Data and Materials: Not applicable.

Ethics Approval: Not applicable.

Conflicts of Interest: The author declares no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:

MFRTAMitochondrial Free Radical Theory of Aging
ROSReactive Oxygen Species
DNMTsDNA Methyltransferases
TCATricarboxylic Acid (cycle)
SLC25A1Citrate Carrier (Solute Carrier Family 25 Member 1)
IDH1Isocitrate Dehydrogenase 1
NAT10N-acetyltransferase 10
CYP2C9Cytochrome P450 Family 2 Subfamily C Member 9
PIK3R1Phosphoinositide-3-Kinase Regulatory Subunit 1
TRRAPTransformation/Transcription Domain Associated Protein
PDCPyruvate Dehydrogenase Complex
GABPAGA Binding Protein Transcription Factor Subunit Alpha
HP1Heterochromatin Protein 1
SUV39H1Suppressor Of Variegation 3-9 Homolog 1
NoRCNucleolar Remodeling Complex
ARID1AAT-Rich Interaction Domain 1A
RTEL1Regulator of Telomere Elongation Helicase 1
TLTelomere Length
TPE-OLDTelomere Position Effect over Long Distance
DSBsDouble-Strand Breaks
HDRHomology-Directed Repair
2-OGDD2-Oxoglutarate-Dependent Dioxygenase
TETTen-Eleven Translocation
SLC25A11 (OGC)Oxoglutarate Carrier
SLC25A10Dicarboxylate Carrier
CIMPCpG Island Methylator Phenotype
PRC2Polycomb Repressive Complex 2
TLS/FUSTranslocated in Liposarcoma/Fused in Sarcoma
SAMS-Adenosylmethionine
PHDsProlyl Hydroxylases
HIF1αHypoxia-Inducible Factor 1-alpha
ALTAlternative Lengthening of Telomeres
DHODHDihydroorotate Dehydrogenase
dNTPsDeoxynucleotide Triphosphates
LSD1Lysine-specific Demethylase 1
ETCElectron Transport Chain
DNA-PKcsDNA-dependent Protein Kinase catalytic subunit
NHEJNon-Homologous End Joining
DDRDNA Damage Response
PGC-1α/βPeroxisome proliferator-activated receptor Gamma Coactivator 1-alpha/beta
PARP-1Poly(ADP-ribose) Polymerase 1
CRM1Chromosome Region Maintenance 1 (Exportin 1)
NESNuclear Export Signal
MTSMitochondrial Targeting Sequence
mtTERTMitochondrial hTERT
RMRPRNA component of Mitochondrial RNA Processing
UNGUracil-DNA Glycosylase
BERBase Excision Repair
CLOCK: BMAL1Circadian Locomotor Output Cycles Kaput: Brain and Muscle ARNT-Like 1
CRCaloric Restriction

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APA Style
Manganelli, M. (2026). The Metabolic-Epigenetic Crosstalk: Mitochondrial Retrograde Signaling in Telomere Homeostasis. BIOCELL, 50(10), 5. https://doi.org/10.32604/biocell.2026.081268
Vancouver Style
Manganelli M. The Metabolic-Epigenetic Crosstalk: Mitochondrial Retrograde Signaling in Telomere Homeostasis. BIOCELL. 2026;50(10):5. https://doi.org/10.32604/biocell.2026.081268
IEEE Style
M. Manganelli, “The Metabolic-Epigenetic Crosstalk: Mitochondrial Retrograde Signaling in Telomere Homeostasis,” BIOCELL, vol. 50, no. 10, pp. 5, 2026. https://doi.org/10.32604/biocell.2026.081268
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