Why is this important?

The researchers discovered that despite differences between mutations, LHON cells shared several common mitochondrial problems. Compared to healthy cells, they produced higher levels of reactive oxygen species, had impaired energy production, and showed abnormalities in autophagy- the cells clean-up and recycling process. Specifically, LHON cells showed signs of a stalled process of autophagy; although the cells could still package damaged proteins and mitochondria into cellular “garbage bins,” a slower removal process led to a greater build-up of waste. 

When the cells were treated with the ACT combination, several positive changes occurred. The treatment reduced oxidative stress, improved mitochondrial respiration (how mitochondria convert nutrients and oxygen into cellular energy), increased the cells’ ability to withstand environmental stressors, and helped “speed up” autophagy, normalizing it to levels seen in healthy cells. In many cases, the improvements were equal to those seen with idebenone. For some outcomes, the ACT supplement combination performed even better. 

One particularly important finding was that ACT worked independently of NQO1 protein levels. While idebenone’s effectiveness appeared closely linked to the amount of NQO1 protein present in the cells, the benefits of ACT did not depend on NQO1. This suggests the supplement combination could potentially be effective in individuals who may not respond optimally to idebenone due to genetic variants in the NQO1 gene. 

The researchers also found that repeated ACT treatment reduced markers of oxidative stress, increased the energy producing units of the mitochondria and overall improved the efficiency of energy production, by promoting the removal of damaged mitochondria, and helping normalize the cellular systems that maintain healthy mitochondria, such as autophagy. 

This study provides evidence that several mitochondrial problems seen in LHON, including oxidative stress, impaired energy production, and disrupted mitochondrial quality control, may be addressed through a multi-ingredient supplement approach. 

Importantly, the research also highlights that mitochondrial diseases involve more than simply reduced energy production. The investigators found that defects in autophagy appear to play an important role in LHON. Understanding these pathways may open new directions for future therapies. 

Because the treatment improved mitochondrial function across multiple LHON mutations and did not rely on NQO1 protein activity, the findings suggest that broader treatment strategies targeting mitochondrial health may have value in genetically diverse patient populations. Although these experiments were conducted in patient-derived cells in the laboratory, the same combination of supplements lowered oxidative stress and lactate in patients with MELAS, CPEO and LHON in a randomized human clinical trial and have been available in Ontario for patients with primary mitochondrial disease for over 20 years though the Inherited Metabolic Disease program. 

Many people living with mitochondrial disease are interested in nutritional and supplement-based approaches that may support mitochondrial health. In this study, researchers from McMaster University investigated whether a laboratory-prepared combination of readily available supplements, including creatine, CoQ10, alpha-lipoic acid, and vitamin E, could improve mitochondrial function in cells taken from people with LHON.

The findings are especially encouraging because the treatment appeared to work across multiple LHON mutations and did not depend on the NQO1 protein levels, a factor that can influence response to idebenone. For families affected by LHON, this research offers another avenue worth exploring in future clinical studies and reinforces the importance of targeting mitochondrial health from multiple angles.

Perhaps most importantly, this study reminds us that even when a disease is caused by a genetic mutation, researchers can still look for ways to strengthen the cell’s resilience, improve mitochondrial function, and help cells better cope with stress. Those approaches may ultimately complement future gene-based therapies and contribute to better outcomes for people living with mitochondrial disease.