bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024‒07‒28
fourteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
  2. The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches.
  3. mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.
  4. Germline regulation of the somatic mitochondrial stress response.
  5. The RNA helicase DHX35 functions as a co-sensor for RIG-I-mediated innate immunity.
  6. Sleep Deprivation Triggers Mitochondrial DNA Release in Microglia to Induce Neural Inflammation: Preventative Effect of Hydroxytyrosol Butyrate.
  7. Mitochondrial inorganic polyphosphate is required to maintain proteostasis within the organelle.
  8. ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse.
  9. BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.
  10. Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
  11. Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
  12. STING: Stay near to STIM(1) neuroprotection.
  13. Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
  14. Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
  1. Int J Mol Sci. 2024 Jul 15. pii: 7738. [Epub ahead of print]25(14):
    PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
    Fedho Kusuma, Soyoung Park, Kim Anh Nguyen, Rosalie Elvira, Duckgue Lee, Jaeseok Han.
      Mitochondrial stress, resulting from dysfunction and proteostasis disturbances, triggers the mitochondrial unfolded protein response (UPRMT), which activates gene encoding chaperones and proteases to restore mitochondrial function. Although ATFS-1 mediates mitochondrial stress UPRMT induction in C. elegans, the mechanisms relaying mitochondrial stress signals to the nucleus in mammals remain poorly defined. Here, we explored the role of protein kinase R (PKR), an eIF2α kinase activated by double-stranded RNAs (dsRNAs), in mitochondrial stress signaling. We found that UPRMT does not occur in cells lacking PKR, indicating its crucial role in this process. Mechanistically, we observed that dsRNAs accumulate within mitochondria under stress conditions, along with unprocessed mitochondrial transcripts. Furthermore, we demonstrated that accumulated mitochondrial dsRNAs in mouse embryonic fibroblasts (MEFs) deficient in the Bax/Bak channels are not released into the cytosol and do not induce the UPRMT upon mitochondrial stress, suggesting a potential role of the Bax/Bak channels in mediating the mitochondrial stress response. These discoveries enhance our understanding of how cells maintain mitochondrial integrity, respond to mitochondrial dysfunction, and communicate stress signals to the nucleus through retrograde signaling. This knowledge provides valuable insights into prospective therapeutic targets for diseases associated with mitochondrial stress.
    Keywords:  PKR; UPRMT; integrated stress response; mitochondrial dsRNAs; mitochondrial stress
    DOI:  https://doi.org/10.3390/ijms25147738
  2. Nucleic Acids Res. 2024 Jul 22. pii: gkae645. [Epub ahead of print]
    The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches.
    Michele Brischigliaro, Annika Krüger, J Conor Moran, Hana Antonicka, Ahram Ahn, Eric A Shoubridge, Joanna Rorbach, Antoni Barrientos.
      The prokaryotic translation elongation factor P (EF-P) and the eukaryotic/archaeal counterparts eIF5A/aIF5A are proteins that serve a crucial role in mitigating ribosomal stalling during the translation of specific sequences, notably those containing consecutive proline residues (1,2). Although mitochondrial DNA-encoded proteins synthesized by mitochondrial ribosomes also contain polyproline stretches, an EF-P/eIF5A mitochondrial counterpart remains unidentified. Here, we show that the missing factor is TACO1, a protein causative of a juvenile form of neurodegenerative Leigh's syndrome associated with cytochrome c oxidase deficiency, until now believed to be a translational activator of COX1 mRNA. By using a combination of metabolic labeling, puromycin release and mitoribosome profiling experiments, we show that TACO1 is required for the rapid synthesis of the polyproline-rich COX1 and COX3 cytochrome c oxidase subunits, while its requirement is negligible for other mitochondrial DNA-encoded proteins. In agreement with a role in translation efficiency regulation, we show that TACO1 cooperates with the N-terminal extension of the large ribosomal subunit bL27m to provide stability to the peptidyl-transferase center during elongation. This study illuminates the translation elongation dynamics within human mitochondria, a TACO1-mediated biological mechanism in place to mitigate mitoribosome stalling at polyproline stretches during protein synthesis, and the pathological implications of its malfunction.
    DOI:  https://doi.org/10.1093/nar/gkae645
  3. Cell Death Dis. 2024 Jul 23. 15(7): 523
    mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.
    Ying Li, Jie Cui, Lei Liu, William S Hambright, Yutai Gan, Yajun Zhang, Shifeng Ren, Xianlin Yue, Liwei Shao, Yan Cui, Johnny Huard, Yanling Mu, Qingqiang Yao, Xiaodong Mu.
      The mechanism regulating cellular senescence of postmitotic muscle cells is still unknown. cGAS-STING innate immune signaling was found to mediate cellular senescence in various types of cells, including postmitotic neuron cells, which however has not been explored in postmitotic muscle cells. Here by studying the myofibers from Zmpste24-/- progeria aged mice [an established mice model for Hutchinson-Gilford progeria syndrome (HGPS)], we observed senescence-associated phenotypes in Zmpste24-/- myofibers, which is coupled with increased oxidative damage to mitochondrial DNA (mtDNA) and secretion of senescence-associated secretory phenotype (SASP) factors. Also, Zmpste24-/- myofibers feature increased release of mtDNA from damaged mitochondria, mitophagy dysfunction, and activation of cGAS-STING. Meanwhile, increased mtDNA release in Zmpste24-/- myofibers appeared to be related with increased VDAC1 oligomerization. Further, the inhibition of VDAC1 oligomerization in Zmpste24-/- myofibers with VBIT4 reduced mtDNA release, cGAS-STING activation, and the expression of SASP factors. Our results reveal a novel mechanism of innate immune activation-associated cellular senescence in postmitotic muscle cells in aged muscle, which may help identify novel sets of diagnostic markers and therapeutic targets for progeria aging and aging-associated muscle diseases.
    DOI:  https://doi.org/10.1038/s41419-024-06863-8
  4. Trends Cell Biol. 2024 Jul 20. pii: S0962-8924(24)00142-9. [Epub ahead of print]
    Germline regulation of the somatic mitochondrial stress response.
    Liankui Zhou, Ying Liu.
      Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans.
    Keywords:  UPR(mt); cell-nonautonomous; germline; mitochondria; stress response
    DOI:  https://doi.org/10.1016/j.tcb.2024.07.004
  5. PLoS Pathog. 2024 Jul;20(7): e1012379
    The RNA helicase DHX35 functions as a co-sensor for RIG-I-mediated innate immunity.
    Yuan Qiao, Shan Zhu, Ning Yang, Shan-Shan Zou, Bao Gao, Jing Wu, Chunyan Liu, Xiaoping Li, Yong-Jun Liu, Jingtao Chen.
      RNA helicases are involved in the innate immune response against pathogens, including bacteria and viruses; however, their mechanism in the human airway epithelial cells is still not fully understood. Here, we demonstrated that DEAH (Asp-Glu-Ala-His) box polypeptide 35 (DHX35), a member of the DExD/H (Asp-Glu-x-Asp/His)-box helicase family, boosts antiviral innate immunity in human airway epithelial cells. DHX35 knockdown attenuated the production of interferon-β (IFN-β), IL6, and CXCL10, whereas DHX35 overexpression increased their production. Upon stimulation, DHX35 was constitutively expressed, but it translocated from the nucleus into the cytosol, where it recognized cytosolic poly(I:C) and poly(dA:dT) via its HELICc domain. Mitochondrial antiviral signaling protein (MAVS) acted as an adaptor for DHX35 and interacted with the HELICc domain of DHX35 using amino acids 360-510. Interestingly, DHX35 interacted with retinoic acid-inducible gene 1 (RIG-I), enhanced the binding affinity of RIG-I with poly(I:C) and poly(dA:dT), and formed a signalsome with MAVS to activate interferon regulatory factor 3 (IRF3), NF-κB-p65, and MAPK signaling pathways. These results indicate that DHX35 not only acted as a cytosolic nucleic acid sensor but also synergized with RIG-I to enhance antiviral immunity in human airway epithelial cells. Our results demonstrate a novel molecular mechanism for DHX35 in RIG-I-mediated innate immunity and provide a novel candidate for drug and vaccine design to control viral infections in the human airway.
    DOI:  https://doi.org/10.1371/journal.ppat.1012379
  6. Antioxidants (Basel). 2024 Jul 12. pii: 833. [Epub ahead of print]13(7):
    Sleep Deprivation Triggers Mitochondrial DNA Release in Microglia to Induce Neural Inflammation: Preventative Effect of Hydroxytyrosol Butyrate.
    Yachong Hu, Yongyao Wang, Yifang Wang, Yuxia Zhang, Zhen Wang, Xiaohong Xu, Tinghua Zhang, Tiantian Zhang, Shuangxi Zhang, Ranrui Hu, Le Shi, Xudong Wang, Jin Li, Hui Shen, Jiankang Liu, Mami Noda, Yunhua Peng, Jiangang Long.
      Sleep deprivation (SD) triggers mitochondrial dysfunction and neural inflammation, leading to cognitive impairment and mental issues. However, the mechanism involving mitochondrial dysfunction and neural inflammation still remains unclear. Here, we report that SD rats exhibited multiple behavioral disorders, brain oxidative stress, and robust brain mitochondrial DNA (mtDNA) oxidation. In particular, SD activated microglia and microglial mtDNA efflux to the cytosol and provoked brain pro-inflammatory cytokines. We observed that the mtDNA efflux and pro-inflammatory cytokines significantly reduced with the suppression of the mtDNA oxidation. With the treatment of a novel mitochondrial nutrient, hydroxytyrosol butyrate (HTHB), the SD-induced behavioral disorders were significantly ameliorated while mtDNA oxidation, mtDNA release, and NF-κB activation were remarkably alleviated in both the rat brain and the N9 microglial cell line. Together, these results indicate that microglial mtDNA oxidation and the resultant release induced by SD mediate neural inflammation and HTHB prevents mtDNA oxidation and efflux, providing a potential treatment for SD-induced mental issues.
    Keywords:  hydroxytyrosol butyrate; microglia; mtDNA release; neural inflammation; oxidative stress; sleep deprivation
    DOI:  https://doi.org/10.3390/antiox13070833
  7. Front Cell Dev Biol. 2024 ;12 1423208
    Mitochondrial inorganic polyphosphate is required to maintain proteostasis within the organelle.
    Renata T Da Costa, Pedro Urquiza, Matheus M Perez, YunGuang Du, Mei Li Khong, Haiyan Zheng, Mariona Guitart-Mampel, Pia A Elustondo, Ernest R Scoma, Vedangi Hambardikar, Beatrix Ueberheide, Julian A Tanner, Alejandro Cohen, Evgeny V Pavlov, Cole M Haynes, Maria E Solesio.
      The existing literature points towards the presence of robust mitochondrial mechanisms aimed at mitigating protein dyshomeostasis within the organelle. However, the precise molecular composition of these mechanisms remains unclear. Our data show that inorganic polyphosphate (polyP), a polymer well-conserved throughout evolution, is a component of these mechanisms. In mammals, mitochondria exhibit a significant abundance of polyP, and both our research and that of others have already highlighted its potent regulatory effect on bioenergetics. Given the intimate connection between energy metabolism and protein homeostasis, the involvement of polyP in proteostasis has also been demonstrated in several organisms. For example, polyP is a bacterial primordial chaperone, and its role in amyloidogenesis has already been established. Here, using mammalian models, our study reveals that the depletion of mitochondrial polyP leads to increased protein aggregation within the organelle, following stress exposure. Furthermore, mitochondrial polyP is able to bind to proteins, and these proteins differ under control and stress conditions. The depletion of mitochondrial polyP significantly affects the proteome under both control and stress conditions, while also exerting regulatory control over gene expression. Our findings suggest that mitochondrial polyP is a previously unrecognized, and potent component of mitochondrial proteostasis.
    Keywords:  mitochondria; mitochondrial inorganic polyphosphate; polyP; protein homeostasis; proteostasis
    DOI:  https://doi.org/10.3389/fcell.2024.1423208
  8. J Neurosci. 2024 Jul 25. pii: e0879242024. [Epub ahead of print]
    ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse.
    Hiu-Tung C Wong, Angelica E Lang, Chris Stein, Catherine M Drerup.
      Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can function to facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial fission and fusion dynamics. VapB is an ER membrane protein present at a subset of ER-mitochondria contact sites. Mutations in VapB cause neurodegenerative disease. Specifically, a proline-to-serine mutation at amino acid 56 (P56S), correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrate that transgenic expression of VapBP56S in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis in zebrafish neurons, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapBP56S transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondria tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.Significance statement Mitochondrial population dysfunction is tightly tied to neurodegenerative diseases, including ALS. Maintenance of the mitochondrial population in neurons requires the birth of new mitochondria and the degradation of damaged organelles. ER-mitochondrial contact site proteins are in a position to regulate both processes in neurons. Our work demonstrates that an ALS-associated mutation in the contact site protein VapB disrupts both processes, identifying VapB as a mediator of regulated mitochondrial turnover to maintain a steady-state mitochondrial population.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0879-24.2024
  9. Brain. 2024 Jul 25. pii: awae241. [Epub ahead of print]
    BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.
    Yang Yang, Hui Chen, Shuwen Huang, Hao Chen, Alexei Verkhratsky, Jianqin Niu, Yibo Qu, Chenju Yi.
      Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer's disease (AD). Promoting mitophagy has been shown to improve cognitive function in AD animals. However, the regulatory mechanism was unclear, which formed the aim of this study. Here, we found that a neuron-specific loss of Bcl-2 family member BOK in AD patients and APPswe/PS1dE9 (APP/PS1) mice is closely associated with mitochondrial damage and mitophagy defects. We further revealed that BOK is the key to the Parkin-mediated mitophagy through competitive binding to the MCL1/Parkin complex, resulting in Parkin release and translocation to damaged mitochondria to initiate mitophagy. Furthermore, overexpressing bok in hippocampal neurons of APP/PS1 mice alleviated mitophagy and mitochondrial malfunction, resulting in improved cognitive function. Conversely, the knockdown of bok worsened the aforementioned AD-related changes. Our findings uncover a novel mechanism of BOK signaling through regulating Parkin-mediated mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in AD, thus representing a promising therapeutic target.
    Keywords:  amyloid-β; cognitive decline; mitochondrial dysfunction; mitophagy; synaptophysin loss
    DOI:  https://doi.org/10.1093/brain/awae241
  10. Nat Metab. 2024 Jul 24.
    Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
    Joshua S Stoolman, Rogan A Grant, Taylor A Poor, Samuel E Weinberg, Karis B D'Alessandro, Jerica Tan, Jennifer Yuan-Shih Hu, Megan E Zerrer, Walter A Wood, Madeline C Harding, Sahil Soni, Karen M Ridge, Paul T Schumacker, G R Scott Budinger, Navdeep S Chandel.
      Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer's disease and the response to demyelinating injury1-5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7-10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.
    DOI:  https://doi.org/10.1038/s42255-024-01080-1
  11. Nat Commun. 2024 Jul 22. 15(1): 6172
    Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
    Benjamin S Johnson, Daniela Farkas, Rabab El-Mergawy, Jessica A Adair, Ajit Elhance, Moemen Eltobgy, Francesca M Coan, Lexie Chafin, Jessica A Joseph, Alex Cornwell, Finny J Johns, Lorena Rosas, Mauricio Rojas, Laszlo Farkas, Joseph S Bednash, James D Londino, Prabir Ray, Anuradha Ray, Valerian Kagan, Janet S Lee, Bill B Chen, Rama K Mallampalli.
      The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.
    DOI:  https://doi.org/10.1038/s41467-024-50031-7
  12. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00541-0. [Epub ahead of print]84(14): 2596-2597
    STING: Stay near to STIM(1) neuroprotection.
    Hong-Gyun Lee, Francisco J Quintana.
      In a recent publication in Cell, Woo et al.1 report that stimulator of interferon genes (STING) links inflammation with glutamate-driven excitotoxicity to induce ferroptosis, identifying a mechanism of inflammation-induced neurodegeneration and also a novel candidate therapeutic target for multiple sclerosis.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.034
  13. Nat Metab. 2024 Jul 24.
    Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
    Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J Pérez-Moreno, María I Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E Rosales-Nieves, Alberto Pascual.
      Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.
    DOI:  https://doi.org/10.1038/s42255-024-01081-0
  14. J Lipid Res. 2024 Jul 20. pii: S0022-2275(24)00106-8. [Epub ahead of print] 100601
    Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
    Kailash Venkatraman, Itay Budin.
      Cardiolipin (CL) is a unique, four-chain phospholipid synthesized in the inner mitochondrial membrane (IMM). The acyl chain composition of CL is regulated through a remodeling pathway, whose loss causes mitochondrial dysfunction in Barth syndrome (BTHS). Yeast has been used extensively as a model system to characterize CL metabolism, but mutants lacking its two remodeling enzymes, Cld1p and Taz1p, exhibit mild structural and respiratory phenotypes compared to mammalian cells. Here we show the essential role of CL remodeling in the structure and function of the IMM in yeast grown under reduced oxygenation. Microaerobic fermentation, which mimics natural yeast environments, caused the accumulation of saturated fatty acids and, under these conditions, remodeling mutants showed a loss of IMM ultrastructure. We extended this observation to HEK293 cells, where iPLA2 inhibition by Bromoenol lactone resulted in respiratory dysfunction and cristae loss upon mild treatment with exogenous saturated fatty acids. In microaerobic yeast, remodeling mutants accumulated unremodeled, saturated CL, but also displayed reduced total CL levels, highlighting the interplay between saturation and CL biosynthesis and breakdown. We identified the mitochondrial phospholipase A1 Ddl1p as a regulator of CL levels, and those of its precursors phosphatidylglycerol and phosphatidic acid, under these conditions. Loss of DDL1 partially rescued IMM structure in cells unable to initiate CL remodeling and had differing lipidomic effects depending on oxygenation. These results introduce a revised yeast model for investigating CL remodeling and suggest that its structural functions are dependent on the overall lipid environment in the mitochondrion.
    Keywords:  Barth Syndrome; Cardiolipin; Lipid saturation; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1016/j.jlr.2024.100601
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