Leigh syndrome disrupts the mitochondria’s ability to produce energy through a process called oxidative phosphorylation. This failure starves cells of ATP, the molecule that powers nearly every function in your body, and hits the brain and nervous system hardest. The condition affects at least 1 in 40,000 newborns and typically appears before age 2.
The Energy Production Breakdown
Mitochondria generate most of a cell’s energy using a chain of five protein complexes, numbered I through V, embedded in the inner mitochondrial membrane. These complexes pass electrons along in sequence, and the energy released at each step is used to produce ATP. In Leigh syndrome, genetic mutations damage one or more of these complexes, and the whole assembly line stalls.
Complex I deficiency is the most common defect. Complex I is the largest of the five complexes and the entry point for the electron chain. When it fails, everything downstream suffers. But Leigh syndrome isn’t limited to one weak link. Complexes II, III, and IV can all be affected depending on the specific mutation a person carries. One of the single most frequent causes involves a protein called SURF1, which helps assemble Complex IV. Without functional SURF1, Complex IV can’t form properly, and electron flow grinds to a halt.
The result is the same regardless of which complex is broken: mitochondria can’t convert food into usable energy efficiently. ATP output drops, and cells that demand the most energy, particularly neurons, are the first to suffer.
Lactic Acid Buildup
When oxidative phosphorylation fails, cells fall back on a less efficient backup system: glycolysis. Glycolysis can produce small amounts of ATP without mitochondria, but it generates lactate as a byproduct. In a healthy body, mitochondria would normally process that lactate further. In Leigh syndrome, they can’t, so lactate and its precursor pyruvate accumulate in the blood, urine, and cerebrospinal fluid.
This buildup is one of the earliest measurable signs of the disease. A lactate-to-pyruvate ratio above 20 in blood or spinal fluid is a strong signal pointing toward mitochondrial dysfunction. Lactate levels in spinal fluid tend to be especially elevated in mitochondrial diseases that affect the brain, and Leigh syndrome is the most common form of those. High levels of the amino acid alanine also appear, because the body converts excess lactate into alanine as another overflow pathway. The persistent acid load from lactate contributes to the metabolic stress that damages tissues over time.
Oxidative Damage to Brain Cells
A stalled electron transport chain doesn’t just make less energy. It also leaks electrons, and those stray electrons react with oxygen to form reactive oxygen species (ROS), which are unstable molecules that damage proteins, membranes, and DNA. In Leigh syndrome, ROS production climbs significantly. Studies on cells taken from patients with Complex I deficiency found elevated ROS levels, and the same has been measured in patients with reduced Complex V activity, who also showed weakened natural antioxidant defenses.
Animal models reveal what this oxidative stress does to the brain. In mice lacking a key Complex I gene, researchers found extensive protein damage in brain tissue driven by a cycle of inflammation: immune-like cells in the brain become overactivated, which promotes neuron death through both programmed self-destruction and direct cellular breakdown. A fruit fly model with a Complex II mutation showed that ROS caused degeneration of synapses and nerve cell bodies, producing a condition closely resembling Leigh syndrome. Notably, that study found ATP levels in the flies remained relatively normal, suggesting that oxidative damage, not just energy depletion, plays a major independent role in destroying brain tissue.
When researchers treated these damaged cells and animals with vitamin E or related antioxidants, ROS levels dropped dramatically and synapse degeneration was prevented, reinforcing that oxidative stress is a direct driver of the neurological damage, not merely a side effect.
Which Brain Regions Are Hit Hardest
The mitochondrial failure in Leigh syndrome produces a distinctive pattern of brain damage visible on MRI: symmetric lesions in the basal ganglia, thalamus, and brainstem. These areas have extremely high energy demands because they coordinate movement, relay sensory information, and regulate basic functions like breathing and swallowing.
The basal ganglia are typically affected first. As the disease progresses, lesions spread to the upper brainstem, then to the lower brainstem. On imaging, these lesions appear as bright spots reflecting sponge-like tissue changes and tiny cavities where cells have died. This pattern is so characteristic that it serves as one of the core diagnostic criteria for the disease, alongside progressive neurological decline and elevated lactate.
This explains the symptoms families see. Infants typically develop normally at first, reaching early milestones like holding up their head. Then, usually between 3 months and 2 years of age, they begin losing those abilities. Difficulty swallowing, low muscle tone, poor reflexes, seizures, and chronic irritability reflect the progressive destruction of these deep brain structures.
The Genetic Roots
Leigh syndrome can arise from mutations in either nuclear DNA or mitochondrial DNA, which makes it genetically complex. Pathogenic variants in at least 98 different nuclear genes have been linked to the condition, inherited through autosomal recessive, autosomal dominant, or X-linked patterns. On the mitochondrial side, the MT-ATP6 gene accounts for roughly 40% of mitochondrial DNA cases, with the m.8993T>G variant being one of the most common.
This genetic diversity is why the disease can look so different from one patient to another. Some mutations knock out Complex I, others cripple Complex IV assembly, and still others disrupt the pyruvate dehydrogenase complex, which feeds fuel into the mitochondrial energy cycle in the first place. The specific mutation influences which tissues are most affected, how quickly the disease progresses, and how severe it becomes. Infants with onset before 6 months face much worse outcomes: in one large study, 40% of early-onset patients had died by the time of analysis, compared to 14% of those whose symptoms began after 6 months. All patients with neonatal onset were either deceased or bedridden, and 80% of those with onset between 1 and 5 months reached the same outcome.
How Current Treatments Target the Mitochondria
There is no cure for Leigh syndrome, but management focuses on supporting whatever mitochondrial function remains and reducing the damage from the dysfunction. The core approach involves a combination of supplements aimed at different parts of the energy production chain.
Coenzyme Q10 (in its more absorbable form, ubiquinol) is central to most treatment regimens. It shuttles electrons between Complexes I, II, and III, so supplementing it can help compensate for partial blockages. It also functions as an antioxidant, helping neutralize the excess ROS that damage brain cells. Riboflavin (vitamin B2) supports Complex I assembly and provides building blocks for a molecule used by Complex II, making it particularly relevant when those complexes are impaired. Thiamine (vitamin B1) targets the pyruvate dehydrogenase complex, the enzyme that converts pyruvate into fuel for the mitochondrial energy cycle.
These supplements are typically combined with additional antioxidants like vitamin E or alpha-lipoic acid to combat oxidative stress. L-arginine has shown benefit specifically for metabolic strokes, a dangerous complication where energy failure causes stroke-like brain damage. Recent long-term data suggest it may improve survival when used in these acute episodes. None of these interventions fix the underlying genetic defect, but they aim to squeeze more function from damaged mitochondria and protect vulnerable tissues from further harm.