Proof-of-concept for synthetic enzyme to treat all mitochondrial disorders.

It is known mitochondria are found in every cell of the human body except red blood cells and are the organelles responsible for producing more than 90% of the energy needed by the body to sustain life and support organ function via conversion of food molecules into the ATP. When mitochondria malfunction, also known as a mitochondrial disorder, organs start to fail, people get sick and even die. Treatment varies from patient to patient and depends on the specific mitochondrial disease diagnosed, however, there is no way to predict a patient’s response to treatment. Now, a study from researchers at Massachusetts General Hospital develops an artificial enzyme that prevents electron build-up in cells caused by malfunctioning mitochondria which could be a therapeutic technique for rare genetic conditions. The team states their artificial enzyme will potentially help a lot of diverse genetic conditions whose final endpoint is redox imbalance. The study is published in the journal Nature Biotechnology.

Previous studies show mitochondrial disorders block the smooth flow of electrons absorbed from food, causing a pileup of electrons, known as a redox imbalance, and stalling vital chemical reactions inside the cell. The excess electrons eventually spill into the blood circulation in the form of lactate, a molecule that serves as a marker for the disease occurring inside the cells, a process known as reductive stress. The current study investigates whether this reductive stress can be alleviated by oxidizing extracellular lactate to pyruvate.

The current study develops a synthetic enzyme called LOXCAT by combining two bacterial proteins, lactate oxidase, and catalase. Results show when LOXCAT is added to cultured human cells with defective mitochondria the artificial enzyme converts lactate to pyruvate, which enters cells and picks up electrons, relieving the electron pileup. Data findings show that pyruvate then converts to lactate, which is released from the cell.

The group observed that LOXCAT reconverts the lactate to pyruvate, which starts the process anew, creating a cycle. The lab states their therapeutic works by directly targeting circulating lactate to safely dissipate excess electrons so redox balance is restored and smooth flow inside the cell resumes. They go on to stress that their enzyme doesn’t have to enter the cell as it operates on the incoming and exiting chemicals to harmonize the cell apparatus.

The team surmises they have engineered a synthetic enzyme to alleviate problems caused by dysfunctional mitochondria. For the future, the researchers state more work needs to be done before LOXCAT is ready for testing in humans.

Source: Massachusetts General Hospital 

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