Small Molecule Modulators for Improving Mitochondrial Dysfunction
These small molecules exhibit modulatory effects on neuronal mitochondrial dynamics for potentially treating patients suffering from neurological or psychiatric disorders. Brain and other central nervous system (CNS) disorders, particularly neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), cause the failure of different cellular and molecular systems for normal brain function. An estimated 6.5 million Americans suffer from a neurological disorder, and by 2030, this number could soar to 12 million if left unchecked as the population ages. The failures of the various systems make the development of new therapies challenging.
The mitochondrial systems in neurons are one of the major failing systems in nearly all brain disorders. It is vital for the function and health of neurons, serving as an energy source through the mitochondrial generation of ATP. Neurodegenerative disorders cause three fundamental impairments to the mitochondrial system by increasing the fragmentation of mitochondria in the disease state and reducing ATP synthesis and the number of mitochondria per neuron. The dysfunction of the neuronal mitochondrial system can be an upstream failure in a cascade of events leading to neuronal cell death.
Researchers at the University of Florida have identified small molecule modulators, with the potential to serve as mitotherapeutics, for treating patients suffering from neurological or psychiatric disorders. These molecules underwent testing for efficacy in human iPSC-derived cortical neurons for Alzheimer’s disease and in lower motor neurons for ALS. They reverse the disease-associated mitochondrial fragmentation, reduced number, and poor function. In some cases, they dramatically increase the survival of the human, diseased neurons in culture.
Application
The identified small molecules or analogs may have efficacy for treating neuropsychiatric disorders, such as Alzheimer’s disease and ALS
Advantages
- Therapeutics modulate neuronal mitostasis, present in most neurological disorders, offering broader protection and higher effectiveness in treating neurodegenerative diseases than currently available therapeutics
- Therapeutics can potentially target the underlying causes of neurological disorders, such as AD, ALS, and PD, transcending treatment of just symptoms
- Drugs may protect the mitochondrial system and perhaps other downstream hallmarks of neurodegenerative disorders like synapse loss or neuroinflammation, increasing the number of potential therapeutic applications
Technology
These small molecules are potential mitotherapeutics for use as modulators of neuronal mitochondrial mitostasis (MnMs), treating neurological or psychiatric disorders. Using a screening tool, researchers focus on parameters like the neuron’s mitochondrial content, mitochondrial elongation and health while testing for potential toxicity. By measuring the electrochemical potential across the inner mitochondrial membrane and ATP generation by the cells, it is possible to identify small molecules to increase mitochondrial function, providing a more biologically relevant high-throughput screening platform for use in brain disease research. The majority of identified mitotherapeutics increase mitochondrial function and protect mitochondria in neurons against insults associated with neuropsychiatric disorders, including oxidative stress, excess glutamate, or Aβ(1-42). Identifying mitotherapeutics enables treating patients suffering from disorders characterized by dysregulated neuronal mitostasis, administering a therapeutically effective amount of the compound in combination with a carrier.
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