Sugar Metabolism Regulates Neuron Survival Following Brain Injury

metabolism Holds Key to Axon Health, New Study Reveals

ANN ARBOR, MI – A groundbreaking study from the University of Michigan has uncovered a surprising link between cellular metabolism adn the health of axons, the vital pathways that transmit signals throughout the nervous system. the research, published in Molecular Metabolism, suggests that how neurons respond to damage isn’t fixed, but rather dynamically shaped by their internal metabolic state.

The study, led by TJ Waller, a postdoctoral fellow at the University of Michigan, focuses on two key proteins: dual leucine zipper kinase (DLK) and Sterile alpha and TIR Motif-containing 1 (SARM1). DLK acts as a sensor for neuronal damage, becoming activated when a cell’s metabolism is disrupted. SARM1, previously known for its role in axon degeneration, appears to be directly coupled with DLK’s response.

Researchers found that when neurons are healthy and axons remain intact, DLK activity increases while SARM1 movement is suppressed – a protective mechanism. However, the study revealed a critical nuance: prolonged activation of DLK can ultimately lead to neurodegeneration, effectively reversing its initial protective effects.

“What surprised us is that the neuroprotective response changes depending on the cell’s internal conditions,” explained study author Dr. Dus. “metabolic signals shape whether neurons hold the line or begin to break down.”

This finding positions DLK as a potential target for treating neurodegenerative diseases. However,controlling its dual nature – its ability to both protect and harm – presents a meaningful challenge.

“If we want to delay the progression of a disease, we want to inhibit its negative aspect,” waller stated. “We want to make sure that we’re not at all inhibiting the more positive aspect that might actually be helping to slow the disease down naturally.”

Understanding the mechanisms that govern DLK’s shift between protective and harmful states could have profound implications for treating neurodegenerative diseases and brain injuries. Dus and Waller emphasize that this research shifts the focus from simply blocking damage to understanding and bolstering the body’s natural defense mechanisms.

“This provides a new perspective on injury and disease, one that goes beyond simply blocking damage to focusing on what the system is already doing to reinforce it,” they concluded.

Reference: Waller TJ, Collins CA, Dus M. Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection. Mol Metab. 2025;98:102187. doi: https://doi.org/10.1016/j.molmet.2025.102187

What are the consequences of both hyperglycemia and hypoglycemia in the context of brain injury recovery?

The Critical Role of Glucose in Neurological Recovery

Following a traumatic brain injury (TBI), stroke, or other neurological event, the brain’s energy demands skyrocket. While often overlooked, sugar metabolism – specifically, glucose utilization – plays a surprisingly pivotal role in determining which neurons survive and which succumb to damage. This isn’t simply about having enough glucose; it’s about how the brain processes it. Understanding this intricate relationship is crucial for developing effective neuroprotective strategies and improving patient outcomes.

Glucose Hypometabolism: A Post-Injury Cascade

One of the earliest and most consistent findings after brain injury is glucose hypometabolism – a reduction in the brain’s ability to utilize glucose. This isn’t a lack of glucose availability (initially), but rather a disruption in the metabolic pathways required to break down glucose and convert it into usable energy (ATP).

Mitochondrial Dysfunction: Damage to mitochondria, the “powerhouses” of cells, is a hallmark of TBI.Impaired mitochondrial function directly hinders glucose oxidation.

Reduced Cerebral Blood Flow: Even without visible damage, blood flow to the injured area frequently enough decreases, limiting glucose delivery.

Inflammation: The inflammatory response following injury consumes significant energy, further exacerbating glucose hypometabolism.

Insulin Resistance: Emerging research suggests that brain injury can induce localized insulin resistance, hindering glucose uptake by neurons.

This energy deficit creates a vicious cycle. Neurons starved of energy become more vulnerable to excitotoxicity, oxidative stress, and ultimately, cell death.

Glycolysis vs. Oxidative Phosphorylation: Shifting Metabolic Priorities

Normally,neurons primarily rely on oxidative phosphorylation – a highly efficient process that uses oxygen to generate ATP from glucose. However, in the aftermath of brain injury, there’s often a shift towards glycolysis – a less efficient, oxygen-autonomous pathway.

Glycolysis Advantages (Short-Term): Glycolysis can provide a rapid, albeit limited, source of ATP even when oxygen is scarce.

Glycolysis Disadvantages (Long-Term): Glycolysis produces lactic acid as a byproduct, leading to acidosis (increased acidity) which can further damage neurons. It also yields significantly less ATP per glucose molecule.

The Warburg Effect: This metabolic shift towards glycolysis, even in the presence of oxygen, is reminiscent of the Warburg effect observed in cancer cells. It highlights the altered metabolic landscape following neurological injury.

The Role of Specific sugar Metabolites

It’s not just glucose itself that matters; the metabolites produced during its breakdown also exert significant influence on neuron survival.

Lactate: While often viewed negatively, lactate can actually serve as an alternative fuel source for neurons, notably in areas with compromised oxidative phosphorylation. It can be shuttled between astrocytes and neurons,providing a crucial energy bridge.

Pyruvate: A key intermediate in glucose metabolism, pyruvate levels can influence neuronal excitability and oxidative stress.

Ketone Bodies: In situations of prolonged glucose hypometabolism, the brain can adapt to utilize ketone bodies – produced from fat breakdown – as an alternative fuel source. This is the principle behind the ketogenic diet (discussed below).

Therapeutic Interventions targeting Sugar Metabolism

Several strategies are being investigated to optimize sugar metabolism and promote neuron survival after brain injury.

1. Glucose Control: Maintaining stable blood glucose levels is paramount. Both hyperglycemia (high blood sugar) and hypoglycemia (low blood sugar) can worsen outcomes.
2. Insulin Sensitization: Research is exploring ways to improve insulin signaling in the brain, enhancing glucose uptake.
3. Mitochondrial Support: Supplementation with compounds like coenzyme Q10 (CoQ10) and creatine may help improve mitochondrial function.
4. Ketogenic Diet: A high-fat, very-low-carbohydrate diet forces the body to produce ketone bodies. Studies suggest that a ketogenic diet can provide neuroprotective benefits after TBI and stroke by providing an alternative energy source and reducing inflammation. Note: This diet should only be implemented under strict medical supervision.
5. Glycolytic Inhibition: Targeting