bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2025–01–26
five papers selected by
Gavin McStay, Liverpool John Moores University
  1. Derivation and Characterization of Isogenic OPA1 Mutant and Control Human Pluripotent Stem Cell Lines.
  2. Fis1 is required for the development of the dendritic mitochondrial network in pyramidal cortical neurons.
  3. Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies.
  4. In vitro stretch modulates mitochondrial dynamics and energy metabolism to induce smooth muscle differentiation in mesenchymal stem cells.
  5. Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease.
  1. Cells. 2025 Jan 17. pii: 137. [Epub ahead of print]14(2):
    Derivation and Characterization of Isogenic OPA1 Mutant and Control Human Pluripotent Stem Cell Lines.
    Katherine A Pohl, Xiangmei Zhang, Johnny Jeonghyun Ji, Linsey Stiles, Alfredo A Sadun, Xian-Jie Yang.
      Dominant optic atrophy (DOA) is the most commonly inherited optic neuropathy. The majority of DOA is caused by mutations in the OPA1 gene, which encodes a dynamin-related GTPase located to the mitochondrion. OPA1 has been shown to regulate mitochondrial dynamics and promote fusion. Within the mitochondrion, proteolytically processed OPA1 proteins form complexes to maintain membrane integrity and the respiratory chain complexity. Although OPA1 is broadly expressed, human OPA1 mutations predominantly affect retinal ganglion cells (RGCs) that are responsible for transmitting visual information from the retina to the brain. Due to the scarcity of human RGCs, DOA has not been studied in depth using the disease affected neurons. To enable studies of DOA using stem-cell-derived human RGCs, we performed CRISPR-Cas9 gene editing to generate OPA1 mutant pluripotent stem cell (PSC) lines with corresponding isogenic controls. CRISPR-Cas9 gene editing yielded both OPA1 homozygous and heterozygous mutant ESC lines from a parental control ESC line. In addition, CRISPR-mediated homology-directed repair (HDR) successfully corrected the OPA1 mutation in a DOA patient's iPSCs. In comparison to the isogenic controls, the heterozygous mutant PSCs expressed the same OPA1 protein isoforms but at reduced levels; whereas the homozygous mutant PSCs showed a loss of OPA1 protein and altered mitochondrial morphology. Furthermore, OPA1 mutant PSCs exhibited reduced rates of oxygen consumption and ATP production associated with mitochondria. These isogenic PSC lines will be valuable tools for establishing OPA1-DOA disease models in vitro and developing treatments for mitochondrial deficiency associated neurodegeneration.
    Keywords:  CRISPR-Cas9 editing; OPA1 gene; dominant optic atrophy; isogenic human pluripotent stem cell lines; mitochondria
    DOI:  https://doi.org/10.3390/cells14020137
  2. bioRxiv. 2025 Jan 07. pii: 2025.01.07.631801. [Epub ahead of print]
    Fis1 is required for the development of the dendritic mitochondrial network in pyramidal cortical neurons.
    Klaudia Strucinska, Parker Kneis, Travis Pennington, Katarzyna Cizio, Patrycja Szybowska, Abigail Morgan, Joshua Weertman, Tommy L Lewis.
      Mitochondrial ATP production and calcium buffering are critical for metabolic regulation and neurotransmission making the formation and maintenance of the mitochondrial network a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously showed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Thus, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture and in vivo , and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 regulates morphological and functional mitochondrial characteristics that influence dendritic tree arborization and connectivity.
    DOI:  https://doi.org/10.1101/2025.01.07.631801
  3. Funct Integr Genomics. 2025 Jan 23. 25(1): 26
    Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies.
    Shiwangi Gupta, Abhinoy Kishore, Vikas Rishi, Aanchal Aggarwal.
      Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca2+) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca2+ homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca2+ regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.
    DOI:  https://doi.org/10.1007/s10142-025-01530-3
  4. FASEB J. 2025 Jan 31. 39(2): e70354
    In vitro stretch modulates mitochondrial dynamics and energy metabolism to induce smooth muscle differentiation in mesenchymal stem cells.
    Yu Liu, Zhijie Yang, Jing Na, Xinyuan Chen, Ziyi Wang, Lisha Zheng, Yubo Fan.
      The smooth muscle cells (SMCs) located in the vascular media layer are continuously subjected to cyclic stretching perpendicular to the vessel wall and play a crucial role in vascular wall remodeling and blood pressure regulation. Mesenchymal stem cells (MSCs) are promising tools to differentiate into SMCs. Mechanical stretch loading offers an opportunity to guide the MSC-SMC differentiation and mechanical adaption for function regeneration of blood vessels. This study shows that cyclic stretch induces the expression of SMC markers α-SMA and SM22 in MSCs. These cells exhibit contractile ability in vitro and facilitate angiogenesis in the Matrigel plug assay in vivo. The contraction of SMCs requires remodeling of their energy metabolism. However, the underlying mechanism in the differentiation of MSCs into SMCs remains to be revealed. Cyclic stretch training promotes glycolysis, oxidative phosphorylation, and mitochondrial fusion and modulates mitochondrial dynamics-related proteins (MFN1, MFN2, DRP1) expression, thereby contributing to MSCs differentiation. Yes-associated protein (YAP) affects mitochondrial dynamics, oxidative phosphorylation, and glycolysis to regulate stretch-mediated differentiation into SMCs. Additionally, Piezo-type mechanosensitive ion channel component 1 (Piezo1) impacts energy metabolism and MSCs differentiation by regulating intracellular Ca2+ levels and YAP nuclear localization. It indicates that YAP can integrate stretch force and energy metabolism signals to regulate the differentiation of MSCs into SMCs.
    Keywords:  cyclic stretch; energy metabolism; mesenchymal stem cells; mitochondrial dynamics; smooth muscle cells
    DOI:  https://doi.org/10.1096/fj.202402944R
  5. Front Pharmacol. 2024 ;15 1474310
    Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease.
    Mengjiao Xu, Peng Feng, Jun Yan, Lei Li.
      Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.
    Keywords:  chronic obstructive pulmonary disease; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial quality control; mitophagy; therapeutic strategies
    DOI:  https://doi.org/10.3389/fphar.2024.1474310
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