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Mitochondrial diseases affect approximately 1 in 5,000 people worldwide, causing debilitating symptoms ranging from muscle weakness to stroke-like episodes. These conditions result from mutations in mitochondrial DNA (mtDNA), which is housed in the mitochondria, the powerhouses of cells. For patients with the common m.3243A>G mutation, treatments remain limited. A fundamental challenge in mitochondrial disease research is that patients typically have a mix of both normal and mutated mtDNA within their cells, known as heteroplasmy.

This condition makes targeted therapies difficult to develop, as the normal-to-mutated mtDNA ratios can vary greatly from tissue to tissue. Current basic research into mtDNA mutations faces significant obstacles due to a lack of disease models. The complex relationship between mutation load and disease severity remains poorly understood because there are no tools to precisely manipulate heteroplasmy levels in either direction.

Against this backdrop, a research team led by Senior Assistant Professor Naoki Yahata from the Department of Developmental Biology, Fujita Health University School of Medicine, Japan, has developed a technology that can modify heteroplasmy levels in cultured cells carrying the m.3243A>G mutation. Their paper was made available online on March 20, 2025, and will be published in Volume 36, Issue 2 of the journal Molecular Therapy Nucleic Acids on June 10, 2025.

The researchers established cultures of patient-derived induced pluripotent stem cells (iPSCs) containing the m.3243A>G mutation and designed two versions of their mtDNA-targeted platinum transcription activator-like effector nucleases (mpTALENs). One version targets mutant mtDNA for destruction, while the other targets normal mtDNA. This bi-directional approach allowed them to generate cells with mutation loads ranging from as low as 11% to as high as 97%, while still maintaining the cells’ ability to differentiate into various tissue types.

The researchers also employed additional techniques, such as uridine supplementation, to establish stable cell lines with different mutation loads. Their results demonstrate that their mpTALEN optimization process created a useful tool for altering heteroplasmy levels in m.3243A>G-iPSCs, improving their potential for studying mutation pathology.

Overall, the study represents a significant advancement in mitochondrial medicine for several reasons. It provides researchers with multiple isogenic cell lines that differ only in their level of heteroplasmy, allowing for a precise study of how mutation load affects disease manifestation. The mpTALEN technology may become therapeutically valuable for reducing mutant mtDNA load in patients.

The proposed method could be adapted for other mutant mtDNAs and may contribute to understanding their associated pathologies and developing new treatments, potentially benefiting patients with various forms of mitochondrial disease.

The human brain is an intricate machine that weighs every social experience, from the warmth of a kind word to the sting of a harsh criticism. Researchers at Mount Sinai have made a groundbreaking discovery about how our brains process positive and negative interactions, shedding light on the underlying neural mechanisms behind common neuropsychiatric disorders like autism spectrum disorder (ASD) and schizophrenia.

For the first time, scientists have identified the specific neural pathways that regulate both positive and negative impressions of social encounters. The study, published in Nature, reveals how an imbalance between these opposing forces can lead to debilitating symptoms in ASD and schizophrenia.

“The ability to recognize and distinguish unpleasant from pleasant interactions is essential for humans to navigate their social environment,” explains Xiaoting Wu, PhD, Assistant Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai. “Until now, it has been unclear how the brain assigns positivity or negativity – ‘valence’ – to social experiences, and how that information can be flexibly updated in a constantly changing environment.”
At the heart of this complex neural circuitry is the hippocampus, a region deep in the temporal lobe responsible for forming new memories, learning, and emotions. Researchers found that two neuromodulators – serotonin and neurotensin – are released into the hippocampal subregion known as ventral CA1, where they control opposing social valence assignment.
While deficits in social valence are prevalent in many neuropsychiatric disorders, their underlying neural mechanisms and pathophysiology have remained elusive. “Through our work we’ve provided the first foundational insights into the neural basis of social valence,” notes Dr. Wu. “We have demonstrated that the neuromodulators serotonin and neurotensin signal opposing valence, revealing a fundamental principle of brain function in the form of a neuromodulatory switch that allows behavioral adaptation based on social history.”

In a novel social cognitive paradigm, researchers exposed mice to negative and positive social encounters. The test mouse was then given the choice between the two, learning to associate one with a positive or negative valence. By activating a specific serotonin receptor in the brain of a mouse model of ASD, researchers were able to restore a positive impression associated with rewarding social experiences.

This breakthrough has significant implications for the development of future therapies targeting common neuropsychiatric disorders. “We identified a specific neuromodulator receptor which we then targeted to rescue social cognitive deficits in a mouse model of ASD,” Dr. Wu explains. “On a broader scale, our work provides critical insights into complex social behaviors while revealing potential therapeutic targets that can be leveraged to improve social cognitive deficits in common neuropsychiatric disorders.”
This research was supported by funding from the NIH K99 Career Development Award, NIMH BRAINS R01 Award, Alkermes Pathways Award, NARSAD Young Investigator Award, and Friedman Brain Institute Scholar Award.

ATP, commonly known as the “fuel” of our cells, has long been thought to be solely responsible for powering cellular processes. However, recent research has revealed that ATP plays a surprising role in preventing harmful protein aggregation associated with neurodegenerative diseases like Parkinson’s and ALS.

In a groundbreaking study published in Science Advances, researchers from the Okinawa Institute of Science and Technology (OIST) have discovered that ATP regulates protein condensation and the overall viscosity of cytoplasm in neurons. When the cytoplasm becomes more viscous, proteins are more prone to aggregate, leading to harmful tangles that damage cells.

Through both in vitro and in vivo trials, the researchers found that boosting ATP production decreases cytosolic viscosity in affected cells, dispersing existing protein aggregates and preventing future pathological aggregations. This finding has significant implications for our understanding of neurodegenerative diseases and may lead to new therapeutic approaches.

In many neurodegenerative diseases, the formation and accumulation of insoluble, membrane-less protein condensates via liquid-liquid phase separation is a common symptom. These protein aggregates can accumulate both inside and outside cells, as seen in late-stage Alzheimer’s disease where they appear as neurofibrillary tangles.

The researchers observed a direct relationship between the intracellular concentration of ATP and the solubility of proteins associated with neurodegenerative disorders like SNCA in Parkinson’s, Tau in Alzheimer’s, and TDP-43 in ALS. They found that boosting ATP production using NMN rescued cytosolic fluidity by breaking up and solubilizing existing protein aggregates in axons from ALS neurons.

This study highlights the complex interplay between cellular energy metabolism and neurodegenerative diseases. While a comprehensive cure for these debilitating conditions is unlikely, this discovery brings us closer to understanding the underlying mechanisms and developing effective treatments.

The researchers’ findings suggest that targeting ATP production may be a viable therapeutic strategy for preventing or alleviating cognitive and motor impairments associated with neurodegenerative diseases. As we continue to unravel the mysteries of cellular metabolism and its connection to disease, we may uncover new avenues for prevention and treatment, ultimately improving the lives of those affected by these debilitating conditions.