Reimagining Neurodegenerative Disorders Through the Lens of Metabolism and Mitochondria

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease (HD) are often viewed through the prism of distinct symptoms and pathology. However, a recent review by Phillips and Picard challenges this perspective, introducing the concept of these conditions as “metabolic icebergs”. This framework emphasizes the underlying role of mitochondrial dysfunction as a unifying factor in their development and progression.

The Metabolic Iceberg Model

The “metabolic iceberg” paradigm reimagines neurodegenerative diseases as consisting of three layers (this is in many ways similar to the Functional Medicine model) – there are some great images in the actual review:

1. The Tip: Observable symptoms like memory loss in AD or motor dysfunction in PD. These are the late-stage effects of prolonged mitochondrial impairment.
2. The Bulk: A hidden layer of widespread mitochondrial dysfunction affecting metabolism, oxidative stress, and cellular processes.
3. The Base: The root causes, including environmental toxins, poor dietary habits, sedentary lifestyles, and genetic predispositions that trigger mitochondrial damage.

Mitochondria: The Core Players

Mitochondria, often called the cell’s powerhouses, are more accurately described as “processors,” orchestrating energy production, metabolic regulation, and cellular signaling. Impaired mitochondrial functions, such as disrupted ATP synthesis and excessive reactive oxygen species (ROS) generation, underlie the progression of neurodegenerative diseases.

Key insights from the review:

• Mitochondrial dysfunction is evident years before clinical symptoms appear, as shown in imaging studies revealing glucose hypometabolism in AD and PD.  This dysfunction is a precursor rather than a consequence of disease, suggesting that early interventions targeting mitochondria could delay or prevent disease progression.
  • Studies using positron emission tomography (PET) and magnetic resonance imaging (MRI) consistently show glucose hypometabolism in specific brain regions long before symptoms emerge:
    • Alzheimer’s Disease (AD): Glucose uptake is significantly reduced in the hippocampus and posterior cingulate cortex, regions critical for memory and cognition.
    • Parkinson’s Disease (PD): Hypometabolism in the substantia nigra and striatum corresponds to early dopamine neuron dysfunction.
  • This means that the lag between mitochondrial dysfunction and symptom onset provides a critical window for therapeutic strategies such as ketogenic diets, which bypass glucose metabolism deficits by providing ketones as an alternative energy source.
• Specific mitochondrial phenotypes, or “mitotypes,” are particularly vulnerable in affected brain regions, leading to the hallmark symptoms of these disorders. This vulnerability may be due to:
  • High-energy demands: Brain regions with high metabolic activity are more reliant on efficient mitochondrial function and are more susceptible to dysfunction.
  • ROS sensitivity: Some mitotypes have lower antioxidant capacities, making them more prone to oxidative damage.
  • Genetic and epigenetic factors: Mitochondrial DNA mutations and epigenetic modifications can further predispose certain mitotypes to dysfunction.

Mitohormesis: A Therapeutic Strategy

The review looks at the application of mitohormesis in neurodegenerative diseases. Mitohormesis refers to the beneficial adaptive responses triggered by mild mitochondrial stress. Strategies to activate mitohormesis include:

• Intermittent Fasting: Encourages mitochondrial turnover (mitophagy), removing damaged mitochondria and promoting biogenesis. This reduces oxidative stress and improves energy production.
• Low-Carbohydrate or Ketogenic Diets: Provide ketones as a cleaner energy source, reducing reactive oxygen species (ROS) while supporting mitochondrial efficiency and resilience.
• Physical Exercise: Induces mitochondrial adaptations through transient oxidative stress, leading to enhanced biogenesis and improved metabolic capacity.

Reframing Neurodegenerative Care

This review underscores the need for a paradigm shift in how we approach neurodegenerative diseases, moving away from a symptomatic treatment model to one that addresses the root causes of disease progression: mitochondrial dysfunction and its upstream drivers.

Current treatments often focus on the visible “tip” of the metabolic iceberg – late-stage clinical symptoms – while the bulk of the disease remains unaddressed. This limited approach risks delaying the progression of neurodegeneration rather than halting or reversing it.

It would seem that a promising alternative would involve targeting mitochondrial health through metabolic recalibration strategies. The idea of recalibrating mitochondrial function through lifestyle and metabolic interventions is a core theme of the review, with strategies like dietary changes, exercise, and toxin reduction highlighted as pathways to improve mitochondrial resilience.

By addressing the “bulk” and “base” of the metabolic iceberg, we can shift toward integrative, preventative, and sustainable approaches to neurodegenerative care. This strategy has the potential to slow or even reverse disease progression, empowering individuals to take a proactive role in maintaining brain health and quality of life.