Leigh Syndrome
https://www.nature.com/articles/s42255-026-01566-0
Mitochondria are often described as the “powerhouses” of cells because they produce energy needed for cells to function. A key part of this process is the electron transport chain, which contains five protein complexes. Complex 1 is the largest and is particularly important for energy production, therefore problems affecting Complex 1 can cause mitochondrial diseases and neurological symptoms. This study investigated whether hypoxia, exposure to lower-than-normal oxygen levels, could help treat mitochondrial disease caused by defects in mitochondrial protein quality control. This study focused on HTRA2, a mitochondrial protease enzyme that helps remove damaged or misfolded proteins. In mice lacking HTRA2, proteins within mitochondria accumulated into harmful clumps. This disrupted Complex 1, reducing mitochondrial oxygen consumption and contributing to neurodegeneration and early death. The researchers found that continuous exposure to hypoxia improved HTRA2-deficient mice. Hypoxia rescued degeneration in the striatum, a brain region involved in movement, and extended lifespan. Experiments suggested that reducing oxygen levels helped restore Complex 1 protein levels and reduced signs of excessive oxygen exposure, known as tissue hyperoxia. The study also identified CLPB, a mitochondrial protein disaggregase (breaks down protein), as a partner of HTRA2. Together, HTRA2 and CLPB help maintain mitochondrial protein quality. Loss of either protein can therefore lead to protein aggregation, Complex 1 instability and disease. These findings suggest that some mitochondrial disorders caused by Complex 1dysfunction may be responsive to hypoxia therapy. Although further research is needed before this approach can be tested clinically, the study highlights oxygen regulation as a promising therapeutic strategy for mitochondrial disease.