Decade-Old Mitochondrial Mystery Resolved

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A decade-old mystery of transport of a key molecule, NAD+, fueling the Mitochondria has been resolved.

This discovery can lead the way to therapeutics for various ailments.

Researchers at Penn Medicine have unveiled the mystery of the vital molecule fueling Mitochondria. This discovery can be exploited to find better treatment for different diseases, from neurodegenerative disorders to cancer.

Researchers from Perelman School of Medicine, University of Pennsylvania, and other institutions found a key gene involved in the transport mechanism in the mitochondria. Nicotinamide adenine dinucleotide (NAD+) is transported to the mitochondria during cellular metabolism. The researchers discovered that transport of NAD+ to mitochondria is dictated by a gene, SLC25A51, in the cell. The chemical energy for the cell is harnessed from nutrients. The decreasing level of NAD+ is an alarming sign of aging. A low level of NAD+ causes diseases including muscular dystrophy and heart failure.

Joseph A. Baur, the co-senior author, said that the critical role of NAD+ in the mitochondria is known for a long time now but how does the molecule reach the organelle was not known. Now that the mystery of how NAD+ is transported has been solved, a whole new area for research has opened.

Xiaolu Ang Cambronne, Ph.D., an assistant professor in the Department of Molecular Biosciences at The University of Texas at Austin, served as a co-senior author.

Several speculations were made about the pathway of NAD+ to the mitochondrial matrix. All hypothesis came to rest when Baur’s lab reported in an eLife study of the fact a transporter being involved in the process in 2018.

A team of researchers then worked on to find the genetic identity of the mitochondrial NAD+ transporter. The researchers considered the SLC25A family. SLC25A family encodes for mitochondrially localized proteins. These proteins carry materials across mitochondrial members.

Timothy S. Luongo, the lead author, a postdoctoral fellow in the Baur lab, said that the genes determined to be essential for cellular viability were focused. NAD+ is a fundamental molecule essential for the maintenance of mitochondrial-mediated energy production. Disruption in the mitochondrial NAD+ transport would affect oxidative phosphorylation resulting in the reduced possibility of cell survival, he mentioned.

A laboratory experiment was performed on the possible role of SLC25A51 in NAD+ transportation. In the experiment, the level of SLC25A51 in the human mitochondria was measured after knocking out SLC25A51 and after overexpressing it. With the help of mitochondrially-targeted NAD+ biosensors, how mitochondria NAD+ levels are controlled by the expression level of the SLC25A51 gene.

The team observed that with the loss of expression of the SLC25A51 gene the mitochondria’s ability to consume oxygen and generate ATP dramatically altered. The change also affected the NAD+ transport into the matrix. In collaboration with the Cambronne lab, the team demonstrated that yeast cells that lack transporter for endogenous mitochondrial NAD+ restored NAD+ mitochondrial transport with the expression of SLC25A51, asserted Luongo.

NAD+ levels can be exploited to treat various diseases, these levels affect uniformly in all parts of the cells, making it a catch-all approach, and it runs the risk of unintended gene expressions or other types of alterations in metabolism. This is the first of the studies to be published where a specific target has been identified by the researchers, which reduces NAD+ levels solely in the mitochondria. It does not affect any other part of the cell.

Exploiting control over NAD+ levels resulting in control over metabolic processes in mitochondria could have major implications on various disease treatments.

A favorable state of respiration to make energy in the cells can be created instead of relying on glycolysis. This can be done by activating the NAD+ transport mechanism. Different cancer types heavily rely on glycolysis for energy. An unfavorable environment for the mechanism can be created with NAD+, or conversely, the highly respiratory cancer cells can be denied of NAD+ supply and forced them to switch to glycolysis for energy.

The heart requires an abundant supply of energy produced in the mitochondria to supply blood to peripheral tissue continuously. A primary reason for heart failure is the dysfunction of the mitochondria. Mitochondrial capacity to transport NAD+ can be targetted to improve the cardiac function of the failing heart.

In respect to exercise, a shift towards more oxidative metabolism for energy could boost endurance immensely.

This work is in its budding days but has opened doors for new investigations concerning mitochondrial NAD+ and its regulation. The researchers will next study about physiological function and regulation mechanism of NAD+ transport. The researchers will also work on turn on or off of the transports independent of gene expression.

Source

NAD+ transport mystery in mitochondria

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