When Energy Runs Low: How Cells Decide What to Save and What to Pause

Connecting mitochondrial stress, the integrated stress response (ISR), and ER proteostasis

In recent years, researchers have increasingly recognized that cells operate under a constant balancing act: energy supply must match the enormous demands of maintaining proteins, metabolism, and repair. When this balance falters, cells activate emergency signaling programs that decide what processes must slow down and what must be protected.

A recent review in Science Signaling explores one of the most important control hubs in this balancing act: the communication between mitochondria and the endoplasmic reticulum (ER) at specialized contact sites known as mitochondria-associated membranes (MAMs). These structures coordinate energy production, protein folding, calcium signaling, and cell survival decisions.

The review highlights how disturbances in either mitochondrial metabolism or ER protein folding activate integrated stress responses that reallocate cellular resources to maintain survival.

The ER: A Protein Factory That Runs on Energy

The ER is responsible for folding and processing many proteins that cells produce. But protein folding is energetically expensive. It requires ATP, redox regulation, and chaperone activity to ensure proteins achieve the correct structure.

Because of this, ER function depends heavily on mitochondrial ATP production.

To coordinate these processes, ER and mitochondria maintain physical contact points—MAMs—that allow rapid exchange of calcium and metabolic signals. Calcium released from the ER stimulates mitochondrial enzymes in the TCA cycle, boosting oxidative phosphorylation and ATP production to meet cellular demand.

In simple terms:

More protein folding demand → more mitochondrial energy production.

When Energy Becomes Limiting

But what happens when mitochondria cannot keep up?

The review highlights an important signaling pathway that connects mitochondrial dysfunction to cellular stress responses.

When mitochondria become impaired, a mitochondrial protease called OMA1 cleaves a signaling protein known as DELE1, which then activates a kinase called HRI. This pathway triggers the Integrated Stress Response (ISR), a central signaling system that allows cells to rapidly adjust protein synthesis and metabolism.

The ISR works by phosphorylating a translation factor called eIF2α, which temporarily reduces global protein synthesis while selectively activating stress-adaptation genes such as ATF4.

In essence, the ISR acts like a resource manager for the cell:

• slow down energy-intensive processes

• prioritize repair and stress adaptation

• attempt to restore metabolic balance.

The ER Stress Response: Another Layer of Protection

When protein folding itself becomes compromised, the ER activates a parallel system known as the Unfolded Protein Response (UPR).

One branch of the UPR involves the sensor PERK, which also feeds into the Integrated Stress Response. PERK phosphorylates eIF2α, producing the same translational slowdown seen during mitochondrial stress.

This convergence is important because it means different cellular problems—energy shortage or protein misfolding—activate the same protective program.

In other words:

Bioenergetic stress and proteostasis stress share a common emergency signaling pathway.

How Stress Signals Remodel Mitochondria

Interestingly, the ISR and UPR do more than simply pause protein production. They also attempt to restore mitochondrial function.

The review describes several adaptive responses triggered by PERK-ISR signaling:

• assembly of mitochondrial respiratory chain supercomplexes

• mitochondrial hyperfusion

• remodeling of mitochondrial cristae

• increased oxidative phosphorylation capacity.

These changes aim to increase cellular energy output, allowing the cell to recover from stress.

A Possible Hierarchy of Stress Responses

Although traditionally ER stress has been viewed as the starting point of the unfolded protein response, emerging evidence suggests a broader perspective.

Mitochondrial dysfunction can directly activate the ISR before overt ER stress develops. When energy supply becomes insufficient:

1. Mitochondrial stress activates ISR

2. Protein synthesis slows

3. Cellular energy is conserved

4. Mitochondrial repair and adaptation are attempted

5. If energy deficits persist, ER proteostasis begins to fail

6. UPR activation intensifies the stress response

This sequence suggests that energy limitation may precede and contribute to proteostasis failure, rather than always occurring as a downstream consequence.

Connecting These Mechanisms to Exposure-Related Malnutrition (ERM)

These findings fit closely with the concept of Exposure-Related Malnutrition (ERM), a framework proposing that chronic environmental and metabolic stress can gradually constrain mitochondrial bioenergetic capacity.

Within this perspective:

• Mitochondrial throughput limitation creates bioenergetic stress

• ISR activation reduces protein synthesis and reallocates resources

• UPR signaling attempts to maintain ER proteostasis

• ER-mitochondria communication adjusts metabolism to restore balance.

When these compensatory mechanisms succeed, cells recover. But when stress persists, and energy production remains constrained, the system can transition from adaptation to chronic dysfunction, contributing to aging and disease.

A Cellular Economy

The emerging picture is that cells operate much like an economic system.

Energy is the currency.

When resources become scarce, the cell must decide:

• which activities to slow down

• which systems to protect

• and how to rebuild its energy supply.

The integrated stress response and the unfolded protein response function as emergency economic policies, coordinating mitochondrial metabolism and protein homeostasis to keep the cellular system stable.

Understanding how these pathways interact may help explain why chronic metabolic stress contributes to aging, inflammation, and degenerative disease—and why restoring mitochondrial resilience may be a key step toward maintaining long-term cellular health.

Reference

Carreras-Sureda A, Kroemer G, Cárdenas JC, Hetz C. (2022). Balancing energy and protein homeostasis at ER–mitochondria contact sites. Science Signaling, 15(741), eabm7524.