Rescuing Lifespan of Leigh Syndrome Mice with NAD+ Regeneration

Mitochondria are specialized structures within living cells critical to generating energy and the building blocks for growth. The dysfunction of mitochondria contributes to degenerative brain diseases, such as Parkinson’s disease and Leigh syndrome, a severe neurological disorder characterized by progressive loss of mental and movement abilities that typically results in death during childhood. Untangling the diverse roles of mitochondria for the maintenance of brain health remains a challenge.

Researchers at Northwestern University Feinberg School of Medicine published a study in Cell Metabolism in which they generated a mouse missing an essential mitochondrial protein complex in the brain to model Leigh syndrome to determine which of the diverse functions of mitochondria is required for brain health. They found that introducing a yeast protein similar to the essential mouse mitochondrial protein complex but without energy production capability in the brains of mice was sufficient to increase their survival. It did not, however, prevent the development of movement and balance problems (i.e., ataxia). These findings suggest that the activity of this essential mitochondrial protein complex in the brain supports organismal survival not through energy production but rather its other roles.

Mitochondrial energy generation and cellular building block production require nicotinamide adenine dinucleotide (NAD+)–an essential cofactor that mediates various reactions through the transfer of electrons between its two forms NAD+ and NADH. NAD+ is regenerated when the electrons from NADH molecules are shuttled into the mitochondria and the electron transport chain–a cluster of proteins that transfer electrons through a membrane within the mitochondria to drive the creation of energy. In addition to driving cellular energy production, the conversion of NADH to NAD+ by the mitochondrial electron transport chain enables the production of the building blocks for amino acids, nucleic acids, carbohydrates, and lipids.

Mitochondrial complex I (MC1)–a group of proteins that form a single multimolecular machine–is a key part of these processes, contributing to energy production and NAD+ regeneration. Dysfunction of MC1 has been implicated in neurodegenerative diseases, such as Parkinson’s disease and Leigh syndrome. Given the essential role of MC1 in both energy production and NAD+ regeneration, it is difficult to parse out which of these functions controls the effects of MC1 dysfunction in complex tissues like the brain. For these reasons, whether NAD+ generation or energy production is dependent on MC1 activity for brain function remains unknown.

The researchers developed a mouse model of Leigh syndrome driven by the loss of an essential subunit of MC1 in the brain that instead produced a similar protein from yeast but with restricted functionality to help determine which of the diverse functions of mitochondria is required for brain health in mice. They used the yeast protein NADH dehydrogenase (NDI1)–a single enzyme that can replace the NAD+ regeneration capability of MC1 but does not contribute to energy production. “We sought to determine whether NAD+ regeneration or bioenergetics is the dominant function of MC1 in protection from brain pathology,” said the authors.

The researchers demonstrated that the yeast NDI1 protein, which regenerates NAD+ without contributing to energy production, is sufficient to increase survival but does not prevent ataxia driven by brain MC1 dysfunction. The presence of NDI1 in the absence of MC1 was sufficient to dramatically prolong lifespan without significantly improving motor function in the Leigh syndrome mouse model.

Therefore, MC1 activity in the brain supports survival through its NAD+ regeneration capacity, while optimal motor control requires the bioenergetics function of MC1. “Overall, our results indicate that a single yeast enzyme capable of regenerating mitochondrial NAD+ from NADH is sufficient to increase the lifespan, but not maintain the motor function, of mice with impairment of MC1 in the brain,” said the authors.