Brain organoids are three-dimensional structures developed from human pluripotent stem cells that can mimic the development and function of the brain. They can also be used to model complex human diseases, study brain development, and screen for potential therapeutic drugs.
A recent review published in The International Journal of Biochemistry & Cell Biology discussed the use of brain organoids in screening for drugs against mitochondrial diseases, which have hitherto presented challenges in treatment due to the complexities of mitochondrial dysfunction.
Study: The application of brain organoid for drug discovery in mitochondrial diseases. Image Credit: Gorodenkoff/Shutterstock.com
Background
Mitochondria are the organelles that carry out oxidative phosphorylation and generate energy through adenosine triphosphate (ATP) for the cell.
Given that the brain is the largest energy consumer, mitochondrial diseases can impact normal brain functions such as cognition, movement, memory, and sensation, among others.
Mutations in the nuclear or mitochondrial deoxyribonucleic acid (DNA) that impact the energy production in the mitochondria can cause dysfunction or even death of neurons, manifesting as movement disorders, seizures, developmental delays, and cognitive impairments.
The lack of appropriate study models and the complexity of mitochondrial diseases have presented challenges in the development of treatment options for mitochondrial diseases.
However, brain organoids, which are developed using patient-specific stem cells, can model mitochondrial diseases that affect the brain, providing an opportunity to screen for potential drugs in a tailored manner.
Brain organoid development
Induced pluripotent stem cells or iPSCs are adult cells that have been reprogrammed to resemble an embryonic stem cell state. Adult cells such as blood and skin cells can be reprogrammed into iPSCs, giving rise to neurons, heart cells, or muscle cells.
These human iPSCs can also be specified according to the genotypic and phenotypic characteristics of a specific mitochondrial disease and therefore, be used as cell models for the specific disease.
Brain organoids can be developed according to the various regions of the brain, such as the cerebral organoid which contains the fore-, mid-, and hindbrain regions and can give rise to other structures such as the hippocampus and cortex.
Brain organoids can also be developed using specific growth factors to model particular regions, such as the striatum, midbrain, hippocampus, forebrain, cerebellum, etc..
Mitochondrial diseases
The mitochondria generate ATP through the tricarboxylic acid cycle or Krebs cycle. However, they also affect apoptosis, calcium signaling, and heme synthesis.
The mitochondria have their DNA, which is different from the nuclear DNA and is inherited from the mother. Some of the genes in the mitochondrial DNA encode proteins that are part of the oxidative phosphorylation chain.
Mitochondrial diseases arise from mutations in the mitochondrial DNA, which impact mitochondrial function and energy production. While these diseases can affect any organ in the body, those that require large amounts of energy, such as the heart, brain, liver, and muscles, are the most affected.
Clinical manifestations can be wide-ranging, impacting the spinal cord and brain, causing seizures, hearing loss, blindness, muscle weakness, and strokes. Kearns-Sayre syndrome results in external ophthalmoplegia, ataxia, and heart block, while Leber’s hereditary optic neuropathy causes vision loss.
Other mitochondrial disorders include mitochondrial myopathies, cardiomyopathy, neuro gastrointestinal encephalomyopathy, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes or MELAS.
Brain organoids for drug screening
The microenvironment and cellular interactions within the brain can be replicated in brain organoids, making them an ideal model to study how mitochondrial dysfunction impacts brain function.
Furthermore, brain organoids created from iPSCs derived from patients with mitochondrial disorders will mimic the patient's genotype and phenotype, allowing the disease mechanisms to be investigated for genetic mutations specific to each mitochondrial disorder.
Brain organoids offer an excellent opportunity to develop personalized medicine. Potential drugs can be tested on patient-specific brain organoids, providing a platform to investigate how specific compounds affect mitochondrial function.
Furthermore, the long-term culturing of brain organoids allows longitudinal study of mitochondrial disease progression.
However, one drawback of reprogramming adult cells to the pluripotent state is the reversal of all the epigenetic markers that contribute to the disease phenotype.
Studies have found that methylation patterns and histone modifications essential for the regulation of mitochondrial genes are reset in iPSCs. Mitigating this problem involves advanced protocols that maintain epigenetic changes to replicate the disease phenotype.
The review also discussed some of the tools used for drug screening involving brain organoids. These include techniques for measuring glycolysis and cellular respiration, observing mitochondrial morphology, metabolomics assessing mitochondrial metabolism, and sequencing methods to identify dysregulated genes and pathways.
Conclusions
To summarize, the review compressively discussed the development of brain organoids using iPSCs, which are reprogrammed adult cells, and using them to study the impact of mitochondrial disorders on brain function and development.
The review also extensively covered the use of brain organoids for screening potential therapeutic drugs to treat mitochondrial disorders by using brain organoids derived from patient-specific cells to replicate the complex genotypic and phenotypic characteristics of mitochondrial diseases.
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