When Metabolism Stalls: How TCA-Cycle Congestion May Help Push Cells Into Senescence

Cellular senescence is often described as the end result of accumulated damage. DNA breaks, oxidative stress, telomere shortening, inflammation, and oncogenic signals eventually persuade a cell to stop dividing.

That explanation is important, but incomplete.

A growing body of research suggests that metabolism is not merely damaged after a cell becomes senescent. The cell’s capacity to transform nutrients into usable energy, maintain redox balance, and support biosynthesis may help determine whether it can continue adapting—or must withdraw from proliferation.

A recent study, “Aging-associated mitochondrial circular RNAs,” adds an unexpected layer to this relationship. The researchers identified a mitochondrial circular RNA that appears to help organize part of the tricarboxylic acid cycle, or TCA cycle. Its decline was associated with aging, mitochondrial dysfunction, and activation of the senescence programme.

The findings suggest that mitochondrial metabolism is regulated not only by enzymes and nutrients, but also by RNA structures that may help metabolic reactions proceed efficiently.

They also raise a broader possibility:

Senescence may sometimes emerge when persistent metabolic congestion makes continued growth, repair, and proliferation energetically unsustainable.

A mitochondrial RNA that declines with age

Circular RNAs are RNA molecules whose ends have been joined to form a closed loop. Unlike conventional messenger RNAs, they often do not encode proteins. Instead, they can bind other RNAs or proteins and influence how cellular processes are organized.

The researchers compared circular RNAs in peripheral blood mononuclear cells from younger men, with an average age of approximately 31 years, and older men, averaging approximately 64 years.

They found a striking reduction in mitochondrial circular RNAs in the older group. Younger participants had 290 circular RNA junctions originating from mitochondrial DNA, compared with only 26 in the older participants.

The most prominent age-related RNA originated from MT-RNR2, the mitochondrial gene that normally produces mitochondrial 16S ribosomal RNA. The circular form, called circMT-RNR2, was abundant in younger blood cells but nearly absent in older cells.

The same pattern appeared in cultured human fibroblasts. As the cells approached replicative senescence, circMT-RNR2 progressively declined.

This did not prove that the RNA loss caused human aging. However, it suggested that circMT-RNR2 may be connected to the metabolic state that distinguishes proliferating cells from senescent ones.

GRSF1 connects mitochondrial RNA processing with metabolism

The researchers then investigated how circMT-RNR2 is maintained.

They focused on GRSF1, an RNA-binding protein found in mitochondrial RNA granules. These granules are sub-mitochondrial compartments in which newly produced mitochondrial RNAs are processed, stabilized, and prepared for use.

GRSF1 directly bound both linear and circular MT-RNR2. Its abundance also declined as fibroblasts became senescent.

When the researchers reduced GRSF1 expression:

• circMT-RNR2 declined;

• mitochondrial transcripts were disrupted;

• succinate and fumarate levels fell;

• the senescence-associated genes p16 and p21 increased.

Reintroducing circMT-RNR2 partially restored the metabolic changes and substantially reduced p16 and p21 expression.

This suggests a pathway in which GRSF1 helps maintain circMT-RNR2, which in turn supports mitochondrial metabolism and helps preserve a proliferating cellular state.

An RNA scaffold for the TCA cycle

Perhaps the most intriguing finding was that circMT-RNR2 interacted with two TCA-cycle enzymes:

• SUCLG1, a component of succinyl-CoA synthetase, which converts succinyl-CoA into succinate;

• SDHA, a component of succinate dehydrogenase, which converts succinate into fumarate.

Succinate dehydrogenase is especially important because it belongs to both the TCA cycle and the electron transport chain. Within the TCA cycle it converts succinate to fumarate. Within the respiratory chain it functions as complex II, transferring electrons toward the ubiquinone pool.

The authors propose that circMT-RNR2 may operate as a molecular scaffold, helping position SUCLG and SDH components near one another so that reactions proceed efficiently.

In simplified form:

Succinyl-CoA → succinate → fumarate

This is more than a sequence of metabolite conversions. It is a junction between carbon metabolism, electron transfer, biosynthesis, redox regulation, and ATP production.

If circMT-RNR2 helps organize this junction, its loss could create resistance within the system—even when the enzymes themselves remain present.

Metabolic decline may precede senescence

The traditional model often runs in one direction:

Cellular damage → senescence → mitochondrial dysfunction

The new findings support an additional direction:

Loss of mitochondrial metabolic coordination → reduced TCA-cycle function → mitochondrial stress → senescence

The study experimentally demonstrated that disrupting GRSF1 and circMT-RNR2 impaired mitochondrial metabolism and increased senescence markers. It did not directly test whether primary TCA-cycle congestion first suppresses GRSF1 or circMT-RNR2.

Nevertheless, the reverse pathway is biologically plausible.

Persistent metabolic congestion could alter:

• mitochondrial membrane potential;

• NADH/NAD⁺ and FAD/FADH₂ balance;

• reactive oxygen species production;

• metabolite availability;

• mitochondrial RNA processing;

• RNA-granule formation;

• GRSF1 stability or RNA-binding activity.

In that case, the relationship could become bidirectional:

TCA congestion

→ impaired GRSF1–circMT-RNR2 function

→ weaker SUCLG–SDH coordination

→ deeper metabolic congestion

→ senescence

Once established, this loop could help stabilize the senescent phenotype.

What does “TCA-cycle congestion” mean?

The TCA cycle is often represented as a circular pathway in a textbook. But inside a living cell, it is not a simple wheel turning at a fixed speed.

It is a dynamic metabolic network whose activity depends on:

• substrate entry;

• enzyme capacity;

• oxygen availability;

• mitochondrial redox state;

• demand for ATP;

• availability of electron acceptors;

• removal of metabolic products;

• withdrawal of intermediates for biosynthesis;

• replenishment through anaplerotic pathways.

Congestion occurs when carbon and reducing equivalents enter the system faster than they can be processed, transferred, or cleared.

This may happen when the electron transport chain cannot adequately oxidize the NADH and FADH₂ produced by the TCA cycle. As NADH accumulates and NAD⁺ becomes less available, several TCA reactions slow. Metabolic intermediates may then accumulate in some locations while becoming deficient in others.

The cycle does not necessarily stop completely. Instead, it becomes uneven, constrained, and increasingly dependent on compensatory pathways.

Cells may respond by:

• increasing lactate production;

• diverting citrate toward lipid synthesis;

• exporting or accumulating succinate;

• relying more heavily on glutamine;

• reducing pyruvate oxidation;

• activating stress signalling;

• slowing protein synthesis and proliferation.

Initially, these adaptations may protect the cell. If the congestion persists, however, they can become part of a maladaptive state.

SDH is a critical intersection between the TCA cycle and the ETC

Succinate dehydrogenase occupies a unique position.

As a TCA-cycle enzyme, it converts succinate to fumarate. As respiratory complex II, it transfers electrons from FADH₂ to ubiquinone.

Its activity therefore depends partly on whether the downstream respiratory system can accept and move those electrons.

When the ubiquinone pool becomes highly reduced or electron transport is limited, complex II activity may slow or even operate differently under certain conditions. Succinate can accumulate, fumarate production can fall, and redox pressure can increase.

Succinate is also a signalling metabolite. Its accumulation can influence hypoxia-inducible signalling, inflammatory pathways, reactive oxygen species production, and enzymes that depend on α-ketoglutarate.

This creates several possible routes from metabolic congestion to senescence:

ETC limitation

→ impaired electron clearance

→ altered SDH activity

→ succinate and redox signalling

→ mitochondrial stress responses

→ p16/p21 activation and growth arrest

However, an important distinction is needed.

Pure SDH inhibition would generally be expected to produce higher succinate and lower fumarate. In the circMT-RNR2 study, GRSF1 depletion reduced both succinate and fumarate.

That pattern suggests something broader than an isolated SDH block. It may reflect reduced upstream succinyl-CoA flux, impaired SUCLG activity, substrate limitation, or generalized suppression of mitochondrial metabolic throughput.

The study therefore fits better with a model of network-level TCA impairment than with simple SDH inhibition alone.

ETC limitation can turn metabolic demand into metabolic pressure

The TCA cycle and electron transport chain are tightly coupled.

The TCA cycle extracts electrons from carbon substrates. The electron transport chain must then transfer those electrons toward oxygen while helping generate the proton gradient needed for ATP synthesis.

When downstream electron flow becomes constrained, upstream metabolism encounters resistance.

This can be understood as bioenergetic impedance:

• Pressure comes from nutrient entry, stress responses, repair demand, and biosynthesis.

• Flow is the transformation of substrates through the TCA cycle and respiratory chain.

• Resistance arises from enzyme limitations, redox imbalance, impaired membranes, restricted oxygen delivery, or reduced electron-acceptor capacity.

• Congestion occurs when pressure continues but flow cannot increase adequately.

A proliferating cell requires substantial metabolic flexibility. It must produce ATP, maintain redox balance, synthesize nucleotides and lipids, repair damage, and duplicate cellular structures.

When mitochondrial throughput becomes persistently constrained, the cell may no longer be able to support all of these tasks simultaneously.

Senescence may then function as a form of cellular allostatic triage:

The cell sacrifices proliferation to preserve short-term survival and prevent replication under metabolically unsafe conditions.

Senescence as an adaptive decision—and a potential trap

Senescence is not inherently pathological.

Temporary growth arrest can protect against cancer, limit the propagation of damaged DNA, support wound healing, and give tissues time to resolve stress.

The problem arises when the initiating stress is not resolved.

A metabolically constrained cell may enter senescence because it cannot safely continue dividing. But the senescent state can then further reduce mitochondrial function, alter nutrient handling, increase inflammatory signalling, and disturb neighbouring cells.

The response becomes self-reinforcing:

Unresolved metabolic impedance

→ senescence

→ reduced mitochondrial flexibility

→ inflammatory and secretory signalling

→ greater tissue-level energetic burden

→ persistence of senescence

This helps explain why removing senescent cells may sometimes improve tissue function but may not fully restore youthful physiology.

If the upstream metabolic and environmental constraints remain, other cells may continue to encounter the same pressure and eventually adopt similar defensive states.

What this study adds

This research does not establish circMT-RNR2 as a master regulator of aging. The human sample was small and cross-sectional, and most mechanistic experiments were performed in cultured fibroblasts.

The proposed scaffolding of TCA-cycle enzymes also requires further confirmation. The study demonstrated RNA–protein interactions and metabolic rescue, but it did not directly visualize circMT-RNR2 assembling an active multienzyme complex or measure complete TCA-cycle flux.

Even so, the study contributes an important principle:

Metabolic performance depends not only on the amount of enzymes or substrates present, but also on how metabolic components are spatially and functionally organized.

The GRSF1–circMT-RNR2 axis may be one element of that organization.

Its decline could impair the coordination of mitochondrial reactions, increase bioenergetic resistance, and lower the cell’s capacity to sustain proliferation. Conversely, chronic TCA and respiratory congestion may damage the RNA-processing environment needed to maintain this axis.

A broader view of metabolism and cellular aging

The relationship between metabolism and senescence is unlikely to be linear.

Metabolic dysfunction can promote senescence, while senescence can further impair metabolism. DNA damage, inflammation, mitochondrial stress, nutrient availability, and redox imbalance all interact within the same network.

The important question may therefore be not simply whether a particular molecule is increased or decreased, but whether the cell can continue transforming energy efficiently enough to:

• meet immediate stress demands;

• maintain redox control;

• repair damage;

• regenerate metabolic capacity;

• and return to flexible baseline regulation.

When that capacity is preserved, cellular stress may remain reversible.

When throughput remains congested and recovery cannot be completed, senescence may become the safest available cellular decision—but also the beginning of a persistent pathological state.

The study of circMT-RNR2 provides a compelling new glimpse into how such a decision might emerge: not only through damage to mitochondrial machinery, but through the loss of the RNA-based organization that helps metabolism flow.

Mun, H., Ham, D.-W., Kim, N. C., Kwon, B.-I., Kim, Y.-K., & Yoon, J.-H. (2026). Aging-associated mitochondrial circular RNAs. Aging, 18(1), 29–43. https://doi.org/10.18632/aging.206354