Abnormal energy production may contribute to the progression of Huntington’s disease, according to a new study.
The study, entitled “The Phasor-FLIM Fingerprints Reveal Shifts From OXPHOS To Enhanced Glycolysis In Huntington Disease,” was recently published in the journal Scientific Reports.
The mechanisms underlying neurodegeneration in Huntington’s disease remain elusive, but compelling evidence suggests that a deficiency in the mitochondria – the cell’s energy powerhouse – contributes to disease progression and weight loss in Huntington’s patients.
In the mitochondria of multiple tissues, several enzymes work together to produce energy that will power the body’s functions. One of these molecules is called NADH. Measuring the activity of NADH provides insight into the status of mitochondrial activity, and can help detect anomalies and metabolic dysfunction that can later be targeted with an appropriate treatment.
NADH carries electrons between reactions of energy production. In the free form, NADH collects electrons from reactions that metabolize fats and sugars from ingested food and, when bound to them, takes them to another set of reactions, called oxidative phosphorylation, which will then allow the production of energetic molecules.
Researchers can track NADH activity by using fluorescent markers. NADH fluorescence is different according to whether it is in the free or bound form.
To understand how the disease would correlate with NADH activity, researchers analyzed the effect of normal and dysfunctional huntingtin (HTT) – the protein underlying Huntington’s pathology – in NADH free and bound forms in cultures of human cells, as well as in the eye discs of fruit flies with Huntington’s disease.
The team used a fluorescent microscopy technique – phasor FLIM – to measure the fractions of free to bound NADH as a way to map metabolic alterations in cells carrying normal and dysfunctional HTT.
The results showed that, both in human cell cultures and in the eye discs of fruit flies, higher levels of free NADH were found in the presence of dysfunctional HTT. This shift toward the free form of NADH may indicate a delay in the production of energy, which can eventually lead to cell death.
Researchers also observed that increased levels in the free form of NADH were associated with dysregulated production of other proteins that participate in other cell processes.
Overall, these findings suggest that changes in NADH activity interrupt the normal production of energy, contributing not only to Huntington’s disease, but potentially other neurodegenerative diseases, such as Alzheimer’s or amyotrophic lateral sclerosis (ALS).
According to the authors, “this powerful label free method can be used to screen native [Huntington’s disease] tissue samples and for potential drug screening.”