🔥 When the Fire Within Burns Too Long: How Mitochondria, Inflammation, and Stress Adaptation Are Connected

What if your immune system wasn’t just reacting to infections—but was also deeply shaped by how your body manages energy and stress over time?

A fascinating new review published in Immunity by Drs. Samuel Weinberg and Navdeep Chandel [2025] reveals just how central our mitochondria—those tiny power plants in our cells—are to the immune system. But more importantly, it shows how energy, stress, and immune balance are intimately linked.

Their findings align perfectly with the Exposure-Related Malnutrition (ERM) framework—an emerging model I’ve developed to understand how chronic stress and environmental exposures silently deplete our body’s reserves, tipping us from adaptation to exhaustion.

🧬 Mitochondria: Not Just Power Plants, but Fire Starters

Traditionally, mitochondria are seen as the engines of the cell, generating ATP. But they also produce reactive oxygen species (ROS)—tiny bursts of molecular “sparks” that can signal other parts of the cell. These mitochondrial ROS (mtROS) are not always bad. In fact, low, well-regulated amounts help the immune system activate and communicate effectively.

But like any spark, too much—and for too long—can start a damaging fire.

The review highlights this duality:

• mtROS from Complex III helps macrophages release IL-10, an anti-inflammatory, calming signal.

• mtROS from Complex I, especially during metabolic stress, increases IL-1β, a pro-inflammatory alarm bell.

• Too much ROS over time leads to immune exhaustion, cell death (like ferroptosis and pyroptosis), and chronic disease.

⚖️ Energy Trade-Offs: The Heart of ERM

This brings us to ERM. In the ERM model, our body is constantly balancing its energy and nutrient resources. When the demands of chronic stress, poor diet, toxins, or infections outpace what the body can supply, it must make trade-offs. That’s adaptation.

But if the stress doesn’t resolve and the nutrient reserves aren’t replenished, those adaptive responses start to degrade the very systems they were trying to protect. That’s when we start seeing fatigue, immune imbalance, inflammation, and organ dysfunction—not as isolated issues, but as signs of systemic adaptive exhaustion.

The review perfectly supports this idea:

• Short-term mtROS help immune cells respond.

• Long-term mtROS drive immune cell dysfunction and exhaustion (especially in T cells).

• Metabolic intermediates like itaconate and fumarate try to slow down inflammation but can backfire under persistent exposure.

In ERM, this is what we call the failure of resolution—when the fire of adaptation never dies down, and the body starts burning its own resources to keep going.

🧠 Immune Burnout Isn’t Just in Your Head

The paper also shows how Th17 cells (pro-inflammatory) and Treg cells (regulatory) behave differently under redox stress:

• A little mitochondrial stress supports Th17 development (defense mode).

• Too much? They collapse, and the immune system becomes erratic.

• Treg cells, which help cool down inflammation, are initially boosted by ROS—but become dysfunctional under chronic mtROS.

This shift—from balanced immune response to runaway inflammation or immune exhaustion—is a hallmark of ERM. It’s not that the immune system is broken. It’s running on empty, stuck in survival mode.

🌱 What This Means for You

If you’re living with chronic fatigue, autoimmune issues, long-COVID, or vague inflammatory symptoms that don’t fit a clear diagnosis, this research is profound.

It suggests:

• Your symptoms might reflect a bioenergetic mismatch, not just a single faulty organ.

• Mitochondrial signaling and redox stress are central to how your immune system copes—or fails to.

• Recovery is possible—but it requires restoring energy balance, resolving stressors, and rebuilding nutrient reserves.

🛠️ A New Way to View Health

This review gives us not just new science—but a new lens. Instead of asking “What’s wrong?” we can ask:

“What system is stuck in adaptation—and what energy or nutrients does it need to recover?”

That’s the essence of ERM. And this research gives us even more confidence that the path to healing starts by understanding the cost of resilience—and helping the body pay back its debt.

📚 Reference:

Weinberg, S. E., & Chandel, N. S. (2025). Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells. Immunity, 58. https://doi.org/10.1016/j.immuni.2025.07.012

#Mitochondrial ROS, #Immune exhaustion, #Stress adaptation, #Exposure-Related Malnutrition (ERM), #Redox signaling