Understanding Mitochondrial Dysfunction in Leigh Syndrome: Can Biogenesis Help?

Published December 2025

Introduction: When Mitochondria Fail at the Genetic Level

Mitochondria are the powerhouses of our cells, generating the energy needed for every cellular function. Leigh syndrome is a severe neurological disorder that primarily affects infants and young children. At its core, it’s a mitochondrial disease caused by mutations in either nuclear DNA, mitochondrial DNA, or both. These genetic errors lead to dysfunctional mitochondria that cannot properly produce ATP—the energy currency cells need to survive.

The Energy Crisis in Leigh Syndrome

Unlike acquired mitochondrial damage that occurs over time, individuals with Leigh syndrome face inherent mitochondrial dysfunction present from birth. The mutations affect the complex assembly of proteins and enzymes needed for oxidative phosphorylation—the process by which mitochondria generate ATP.

Healthy cells manage mitochondrial health through mitophagy, a cleanup process that identifies and breaks down damaged mitochondria. In Leigh syndrome, however, the higher prevalence of damaged mitochondria creates chronic, overwhelming stress. Cells struggle to keep pace with the continuous influx of dysfunctional organelles.

This creates a cruel paradox: you need energy to clean up your energy-producing machinery. Cells need ATP to manage their burden of dysfunctional mitochondria, but the very organelles that should provide this energy are compromised. As energy supplies become depleted, cellular cleanup systems slow down or stall. Damaged mitochondria accumulate, fail to produce adequate energy, and increase oxidative stress, leading to the progressive symptoms characteristic of Leigh syndrome.

Reversing the Tide: Increasing Healthy Mitochondria

If the core problem is an energy crisis, what if we could increase the supply of healthy mitochondria? By providing cells with additional functional mitochondria, we potentially give them the energy resources needed to support mitophagy, manage oxidative stress more effectively, maintain essential cellular functions, and rebalance toward a healthier state.

This approach doesn’t eliminate the genetic mutations causing the problem. Instead, it aims to shift the balance within cells, providing enough functional capacity that cells can better cope with their ongoing challenges.

Won’t Biogenesis Create More Bad Mitochondria?
The critical question: If genetic instructions for creating mitochondria are flawed, won’t making more simply create more dysfunctional ones?

The answer is nuanced: Generally not, though the possibility exists. The preponderance of evidence suggests that increasing mitochondrial biogenesis typically helps rather than harms, even with genetic mutations present.

Heteroplasmy: The Natural Coexistence of Good and Bad

Heteroplasmy describes when both dysfunctional and healthy mitochondria coexist within cells. In Leigh syndrome, cells contain mixtures, some mitochondria with severe mutations, others with milder defects or relatively normal function. Here’s the key insight: heteroplasmy isn’t unique to disease. It’s natural and increases in everyone with age through oxidative damage and replication errors.

Consider exercise, the best-known trigger for mitochondrial biogenesis. Does exercise create some damaged mitochondria along with healthy ones? Probably. Yet evidence overwhelmingly shows exercise benefits health and cellular function, even in aging populations.

Why? Mitochondrial biogenesis involves more than simple replication: damaged mitochondria are preferentially targeted for removal through quality control mechanisms, the overall increase in mitochondrial mass provides more total functional capacity, and more mitochondria mean more ATP for better quality control.

In Leigh syndrome, heteroplasmy occurs at accelerated rates, but fundamental principles remain similar. The question isn’t whether biogenesis might create some dysfunctional mitochondria, but whether the net effect improves cellular function.

The Scientific Evidence

Multiple lines of evidence support biogenesis being beneficial despite genetic mutations: clinical observations haven’t shown the worsening expected if biogenesis primarily created dysfunctional mitochondria, exercise-induced biogenesis remains beneficial despite increasing heteroplasmy throughout life, selective mitophagy and functional selection explain why biogenesis improves net function, and more total mitochondria provide more ATP, enabling better cellular management.

Conclusion

Leigh syndrome represents one of the most challenging genetic diseases. The emerging understanding of mitochondrial biogenesis offers a different paradigm, not correcting mutations directly, but shifting cellular balance by providing additional functional capacity.

This approach doesn’t cure Leigh syndrome, but by supporting natural capacity for mitochondrial renewal, there may be a pathway toward improved cellular function and quality of life.

Watch this video to learn more about the role of mitochondria in Leigh Syndrome.