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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 discovery of how impaired mitochondrial dynamics and quality control mechanisms contribute to insulin resistance related to type 2 diabetes has shed new light on the complex interplay between mitochondria and metabolic health. Researchers at Pennington Biomedical Research Center have made groundbreaking findings, published in the Journal of Cachexia, Sarcopenia and Muscle, that reveal critical insights into how certain enzymes regulate mitochondrial dynamics within skeletal muscle.

The study, led by Dr. John Kirwan, Executive Director of Pennington Biomedical, focused on the significance of deubiquitinating enzymes (DUBs) in maintaining mitochondrial quality control. The research team found that impaired mitophagy, the process by which cells remove damaged mitochondria, can lead to mitochondrial fragmentation as a compensatory mechanism. This adaptation allows skeletal muscle cells to sustain function despite metabolic challenges.

In individuals with type 2 diabetes, a specific protein called dynamin-related protein 1 (DRP1) is overactive, causing an imbalance in mitochondrial dynamics. Furthermore, the team discovered that certain DUBs interfere with mitophagy, making it more difficult for muscles to use insulin properly. This intricate interplay between mitochondria and insulin sensitivity has significant implications for our understanding of type 2 diabetes.

The research findings advance the knowledge on how impaired mitochondrial dynamics and quality control contribute to skeletal muscle insulin resistance and the manifestation of type 2 diabetes. Moreover, they provide crucial evidence that DUB antagonists may play a vital role in preventing or treating type 2 diabetes.

“Our study highlights the complex relationship between mitochondria and insulin,” said Dr. Kirwan. “We are excited about the potential for future interventions aimed at improving metabolic health, particularly in the context of type 2 diabetes.”

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.