bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–08–18
twelve papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
  2. MSC-mediated mitochondrial transfer restores mitochondrial DNA and function in neural progenitor cells of Leber's hereditary optic neuropathy.
  3. Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome.
  4. A multiple animal and cellular models approach to study frataxin deficiency in Friedreich Ataxia.
  5. Dysregulation of mitochondria, apoptosis and mitophagy in Leber's hereditary optic neuropathy with MT-ND1 3635G>A mutation.
  6. Extracellular vesicles: opening up a new perspective for the diagnosis and treatment of mitochondrial dysfunction.
  7. OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
  8. Mitochondrial network reorganization and transient expansion during oligodendrocyte generation.
  9. Fine-tuning AMPK in physiology and disease using point-mutant mouse models.
  10. Benzopyrene represses mitochondrial fission factors and PINK1/Parkin-mediated mitophagy in primary astrocytes.
  11. A Barth Syndrome Patient-Derived D75H Point Mutation in TAFAZZIN Drives Progressive Cardiomyopathy in Mice.
  12. Pregnancy-induced metabolic reprogramming and regenerative responses to pro-aging stresses.
  1. Nat Commun. 2024 Aug 12. 15(1): 6914
    Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    Abhishek Aich, Angela Boshnakovska, Steffen Witte, Tanja Gall, Kerstin Unthan-Fechner, Roya Yousefi, Arpita Chowdhury, Drishan Dahal, Aditi Methi, Svenja Kaufmann, Ivan Silbern, Jan Prochazka, Zuzana Nichtova, Marcela Palkova, Miles Raishbrook, Gizela Koubkova, Radislav Sedlacek, Simon E Tröder, Branko Zevnik, Dietmar Riedel, Susann Michanski, Wiebke Möbius, Philipp Ströbel, Christian Lüchtenborg, Patrick Giavalisco, Henning Urlaub, Andre Fischer, Britta Brügger, Stefan Jakobs, Peter Rehling.
      Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-51109-y
  2. Sci China Life Sci. 2024 Aug 08.
    MSC-mediated mitochondrial transfer restores mitochondrial DNA and function in neural progenitor cells of Leber's hereditary optic neuropathy.
    Rui Wang, Feixiang Bao, Manjiao Lu, Xiaoyun Jia, Jiahui Xiao, Yi Wu, Qingjiong Zhang, Xingguo Liu.
      Leber's hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA (mtDNA). Unfortunately, the available treatment options for LHON patients are limited due to challenges in mitochondrial replacement. In our study, we reprogramming LHON urine cells into induced pluripotent stem cells (iPSCs) and differentiating them into neural progenitor cells (NPCs) and neurons for disease modeling. Our research revealed that LHON neurons exhibited significantly higher levels of mtDNA mutations and reduced mitochondrial function, confirming the disease phenotype. However, through co-culturing LHON iPSC-derived NPCs with mesenchymal stem cells (MSCs), we observed a remarkable rescue of mutant mtDNA and a significant improvement in mitochondrial metabolic function in LHON neurons. These findings suggest that co-culturing with MSCs can enhance mitochondrial function in LHON NPCs, even after their differentiation into neurons. This discovery holds promise as a potential therapeutic strategy for LHON patients.
    Keywords:  energy; induced pluripotent stem cells; mesenchymal stem cells; metabolism; mitochondria; mitochondrial DNA; mitochondrial diseases; stem cells
    DOI:  https://doi.org/10.1007/s11427-024-2647-8
  3. Neurol Neurochir Pol. 2024 Aug 12.
    Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome.
    Kamil Dzwilewski, Karol Chojnowski, Magdalena Krygier, Marta Zawadzka, Magdalena Chylińska, Maria Mazurkiewicz-Bełdzińska.
      
    Keywords:  DNAJC30; Leigh Syndrome; dystonia; idebenone; mitochondrial disease; optic neuropathy
    DOI:  https://doi.org/10.5603/pjnns.100423
  4. Biochim Biophys Acta Mol Cell Res. 2024 Aug 11. pii: S0167-4889(24)00152-6. [Epub ahead of print]1871(7): 119809
    A multiple animal and cellular models approach to study frataxin deficiency in Friedreich Ataxia.
    Valentine Mosbach, Hélène Puccio.
      Friedreich's ataxia (FA) is one of the most frequent inherited recessive ataxias characterized by a progressive sensory and spinocerebellar ataxia. The main causative mutation is a GAA repeat expansion in the first intron of the frataxin (FXN) gene which leads to a transcriptional silencing of the gene resulting in a deficit in FXN protein. The nature of the mutation (an unstable GAA expansion), as well as the multi-systemic nature of the disease (with neural and non-neural sites affected) make the generation of models for Friedreich's ataxia quite challenging. Over the years, several cellular and animal models for FA have been developed. These models are all complementary and possess their own strengths to investigate different aspects of the disease, such as the epigenetics of the locus or the pathophysiology of the disease, as well as being used to developed novel therapeutic approaches. This review will explore the recent advancements in the different mammalian models developed for FA.
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119809
  5. Gene. 2024 Aug 13. pii: S0378-1119(24)00734-0. [Epub ahead of print] 148853
    Dysregulation of mitochondria, apoptosis and mitophagy in Leber's hereditary optic neuropathy with MT-ND1 3635G>A mutation.
    Yingqi Chen, Xiaoyang Wei, Xiaorui Ci, Yanchun Ji, Juanjuan Zhang.
      Leber's hereditary optic neuropathy (LHON) is a maternal inherited disorder, primarily due to mitochondrial DNA (mtDNA) mutations. This investigation aimed to assess the pathogenicity of m.3635G>A alteration known to confer susceptibility to LHON. The disruption of electrostatic interactions among S110 of the MT-ND1 and the side chain of E4, along with the carbonyl backbone of M1 in the NDUFA1, was observed in complex I of cybrids with m.3635G>A. This disturbance affected the complex I assembly activity by changing the mitochondrial respiratory chain composition and function. In addition, the affected cybrids exhibited notable deficiencies in complex I activities, including impaired mitochondrial respiration and depolarization of its membrane potential. Apoptosis was also stimulated in the mutant group, as witnessed by the secretion of cytochrome c and activation of PARP, caspase 3, 7, and 9 compared to the control. Furthermore, the mutant group exhibited decreased levels of autophagy protein light chain 3, accumulation of autophagic substrate P62, and impaired PINK1/Parkin-dependent mitophagy. Overall, the current study has confirmed the crucial involvement of the alteration of the m.3635G>A gene in the development of LHON. These findings contribute to a deeper comprehension of the pathophysiological mechanisms underlying LHON, providing a fundamental basis for further research.
    Keywords:  Apoptosis; Leber’s hereditary optic neuropathy (LHON); MT-ND1 mutation; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.gene.2024.148853
  6. J Nanobiotechnology. 2024 Aug 14. 22(1): 487
    Extracellular vesicles: opening up a new perspective for the diagnosis and treatment of mitochondrial dysfunction.
    Jiali Li, Tangrong Wang, Xiaomei Hou, Yu Li, Jiaxin Zhang, Wenhuan Bai, Hui Qian, Zixuan Sun.
      Mitochondria are crucial organelles responsible for energy generation in eukaryotic cells. Oxidative stress, calcium disorders, and mitochondrial DNA abnormalities can all cause mitochondrial dysfunction. It is now well documented that mitochondrial dysfunction significantly contributes to the pathogenesis of numerous illnesses. Hence, it is vital to investigate innovative treatment methods targeting mitochondrial dysfunction. Extracellular vesicles (EVs) are cell-derived nanovesicles that serve as intercellular messengers and are classified into small EVs (sEVs, < 200 nm) and large EVs (lEVs, > 200 nm) based on their sizes. It is worth noting that certain subtypes of EVs are rich in mitochondrial components (even structurally intact mitochondria) and possess the ability to transfer them or other contents including proteins and nucleic acids to recipient cells to modulate their mitochondrial function. Specifically, EVs can modulate target cell mitochondrial homeostasis as well as mitochondria-controlled apoptosis and ROS generation by delivering relevant substances. In addition, the artificial modification of EVs as delivery carriers for therapeutic goods targeting mitochondria is also a current research hotspot. In this article, we will focus on the ability of EVs to modulate the mitochondrial function of target cells, aiming to offer novel perspectives on therapeutic approaches for diverse conditions linked to mitochondrial dysfunction.
    Keywords:  Biomarkers; Extracellular vesicles; Mitochondrial dysfunction; Pathogenesis; Targeted therapies
    DOI:  https://doi.org/10.1186/s12951-024-02750-8
  7. Mol Cell. 2024 Aug 09. pii: S1097-2765(24)00618-X. [Epub ahead of print]
    OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
    Felix G Liang, Fereshteh Zandkarimi, Jaehoon Lee, Joshua L Axelrod, Ryan Pekson, Yisang Yoon, Brent R Stockwell, Richard N Kitsis.
      Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.
    Keywords:  ATF4; GPx4; OPA1; cell death; ferroptosis; integrated stress response; mitochondria; system X(c)(−); xCT
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.020
  8. Nat Commun. 2024 Aug 14. 15(1): 6979
    Mitochondrial network reorganization and transient expansion during oligodendrocyte generation.
    Xhoela Bame, Robert A Hill.
      Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes of the brain. This process persists throughout life and is essential for recovery from neurodegeneration. To better understand the cellular checkpoints that occur during oligodendrogenesis, we determined the mitochondrial distribution and morphometrics across the oligodendrocyte lineage in mouse and human cerebral cortex. During oligodendrocyte generation, mitochondrial content expands concurrently with a change in subcellular partitioning towards the distal processes. These changes are followed by an abrupt loss of mitochondria in the oligodendrocyte processes and myelin, coinciding with sheath compaction. This reorganization and extensive expansion and depletion take 3 days. Oligodendrocyte mitochondria are stationary over days while OPC mitochondrial motility is modulated by animal arousal state within minutes. Aged OPCs also display decreased mitochondrial size, volume fraction, and motility. Thus, mitochondrial dynamics are linked to oligodendrocyte generation, dynamically modified by their local microenvironment, and altered in the aging brain.
    DOI:  https://doi.org/10.1038/s41467-024-51016-2
  9. Dis Model Mech. 2024 Aug 01. pii: dmm050798. [Epub ahead of print]17(8):
    Fine-tuning AMPK in physiology and disease using point-mutant mouse models.
    Naghmana Ashraf, Jeanine L Van Nostrand.
      AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that monitors the cellular energy status to adapt it to the fluctuating nutritional and environmental conditions in an organism. AMPK plays an integral part in a wide array of physiological processes, such as cell growth, autophagy and mitochondrial function, and is implicated in diverse diseases, including cancer, metabolic disorders, cardiovascular diseases and neurodegenerative diseases. AMPK orchestrates many different physiological outcomes by phosphorylating a broad range of downstream substrates. However, the importance of AMPK-mediated regulation of these substrates in vivo remains an ongoing area of investigation to better understand its precise role in cellular and metabolic homeostasis. Here, we provide a comprehensive overview of our understanding of the kinase function of AMPK in vivo, as uncovered from mouse models that harbor phosphorylation mutations in AMPK substrates. We discuss some of the inherent limitations of these mouse models, highlight the broader implications of these studies for understanding human health and disease, and explore the valuable insights gained that could inform future therapeutic strategies for the treatment of metabolic and non-metabolic disorders.
    Keywords:  AMPK; Cell signaling; Mouse models
    DOI:  https://doi.org/10.1242/dmm.050798
  10. Toxicology. 2024 Aug 13. pii: S0300-483X(24)00207-5. [Epub ahead of print] 153926
    Benzopyrene represses mitochondrial fission factors and PINK1/Parkin-mediated mitophagy in primary astrocytes.
    Yunn Me Me Paing, Yunkyung Eom, Sung Hoon Lee.
      Mitochondria are essential for various physiological functions in astrocytes in the brain, such as maintaining ion and pH homeostasis, regulating neurotransmission, and modulating neuroinflammation. Mitophagy, a form of autophagy specific to mitochondria, is essential for ensuring mitochondrial quality and function. Benzo[a]pyrene (BaP) accumulates in the brain, and exposure to it is recognized as an environmental risk factor for neurodegenerative diseases. However, while the toxic mechanisms of BaP have been investigated in neurons, their effects on astrocytes-the most prevalent glial cells in the brain-are not clearly understood. Therefore, this study aims to investigate the toxic effects of exposure to BaP on mitochondria in primary astrocytes. Fluorescent probes and genetically encoded indicators were utilized to visualize mitochondrial morphology and physiology, and regulatory factors involved in mitochondrial morphology and mitophagy were assessed. Additionally, the mitochondrial respiration rate was measured in BaP-exposed astrocytes. BaP exposure resulted in mitochondrial enlargement owing to the suppression of mitochondrial fission factors. Furthermore, BaP-exposed astrocytes demonstrated reduced mitophagy and exhibited aberrant mitochondrial function and physiology, such as altered mitochondrial respiration rates, increased mitochondrial superoxide, disrupted mitochondrial membrane potential, and dysregulated mitochondrial Ca2+. These findings offer insights into the underlying toxic mechanisms of BaP exposure in neurodegenerative diseases by inducing aberrant mitophagy and mitochondrial dysfunction in astrocytes.
    Keywords:  astrocytes; benzo[a]pyrene; fission factor; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.tox.2024.153926
  11. Int J Mol Sci. 2024 Jul 27. pii: 8201. [Epub ahead of print]25(15):
    A Barth Syndrome Patient-Derived D75H Point Mutation in TAFAZZIN Drives Progressive Cardiomyopathy in Mice.
    Paige L Snider, Elizabeth A Sierra Potchanant, Zejin Sun, Donna M Edwards, Ka-Kui Chan, Catalina Matias, Junya Awata, Aditya Sheth, P Melanie Pride, R Mark Payne, Michael Rubart, Jeffrey J Brault, Michael T Chin, Grzegorz Nalepa, Simon J Conway.
      Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele (TazPM) that phenocopies BTHS clinical traits. As TazPM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile TazPM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile TazPM hearts. However, adult TazPM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult TazPM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.
    Keywords:  Barth syndrome; mitochondria; p53 pathway; patient-tailored Tafazzin mutant allele; progressive cardiomyopathy
    DOI:  https://doi.org/10.3390/ijms25158201
  12. Trends Endocrinol Metab. 2024 Aug 08. pii: S1043-2760(24)00192-9. [Epub ahead of print]
    Pregnancy-induced metabolic reprogramming and regenerative responses to pro-aging stresses.
    Dainan Yu, Lanfang Luo, Hongmei Wang, Ng Shyh-Chang.
      Pregnancy is associated with physiological adaptations that affect virtually all organs, enabling the mother to support the growing fetus and placenta while withstanding the demands of pregnancy. As a result, mammalian pregnancy is a unique state that exerts paradoxical effects on maternal health. On one hand, the metabolic stress induced by pregnancy can accelerate aging and functional decline in organs. On the other hand, pregnancy activates metabolic programming and tissue regenerative responses that can reverse age-related impairments. In this sense, the oocyte-to-blastocyst transition is not the only physiological reprogramming event in the mammalian body, as pregnancy-induced regeneration could constitute a second physiological reprogramming event. Here, we review findings on how pregnancy dualistically leads to aging and rejuvenation in the maternal body.
    Keywords:  aging; metabolic reprogramming; metabolic syndrome; pregnancy; pregnancy-related diseases; tissue regeneration and rejuvenation
    DOI:  https://doi.org/10.1016/j.tem.2024.07.011
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