5-aminolevulinic acid can help fight mitochondrial disorders

Tokyo, Japan – Scientists from Tokyo Metropolitan University have shown that 5-aminolevulinic acid (5-ALA) helps overcome deficiencies in Complex I (CI), the first in a series of protein complexes that transport electrons and help move mitochondria. They showed that fruit flies that lost their protein analogues showed improved health when given a mixture of drugs including 5-ALA. CI deficiency is responsible for most mitochondrial disorders; the team’s findings might lead to new therapies.

Mitochondrial diseases arise from problems with the mitochondria, the tiny organelles in cells that produce adenosine triphosphate (ATP), the chemical fuel that powers many of the biochemical processes in our bodies. Problems are particularly acute in more energy-intensive parts of the body such as the brain and muscles, causing severe problems such as mitochondrial encephalopathy, lactic acidosis and stroke-like episode syndrome (MELAS), a debilitating condition. Unfortunately, there is currently no cure: scientists around the world are in constant search of an effective treatment.

Complex I (CI) deficiency is a common cause of mitochondrial disorders. Complex I is the first in a series of protein complexes that help transport electrons to generate reactions in the mitochondria that ultimately lead to the production of ATP. However, this is not the only way ATP is made; it is known that Complexes II, III, IV and cytochrome c can also provide electrons for the same process, but whether these can be utilized against CI deficiency is unknown.

Now, a team led by Associate Professor Kanae Ando of Tokyo Metropolitan University has shown that certain chemical supplements can help selectively increase CII and CIV to overcome CI deficiencies. They studied the artificially reduced CI equivalent of fruit flies; flies with this genetic “knockdown” show problems with their locomotion and shorter life spans. However, they found that giving them a mixture of 5-aminopulnic acid and sodium ferrous citrate (SFC) helped improve their locomotor function and the development of their neuromuscular junctions. The ATP level also increased significantly, but this was not due to an increase in the number of CIs.

On closer inspection, the team confirmed that the activity of Complex II and IV was increased and helped overcome the problems associated with CI deficiency. 5-ALA is known as a heme precursor, an important part of the function of Complexes II, III, IV and cytochrome c. When fed 5-ALA, fruit flies exhibited metabolic changes that use their CII and CIV abilities to transport electrons and drive ATP production. They also noticed that CI-deficient flies had increased levels of pyruvate and lactate in their cells, much like CI-deficient human patients suffering from lactic acidosis. 5-ALA also helps lower levels of both.

Regardless of the severity of mitochondrial disorders, there is no treatment yet that addresses the root cause of many of the health problems it may cause. The team’s findings hold promise not only for new insights but also for potentially new therapeutic options for a whole class of deadly diseases.

This work was supported by the Japan Foundation for Aging and Health, Grant-in-Aid for Scientific Research on Challenging Research (Exploratory) (JSPS KAKENHI Grant No. 19K21593), and SBI Pharmaceuticals Co., Ltd.