bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒03‒17
twenty-one papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico 
  1. Mitochondrial complex I activity in microglia sustains neuroinflammation.
  2. Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant.
  3. Generation and characterization of iPSC lines from Friedreich's ataxia patient (FRDA) with GAA.TTC repeat expansion in the Frataxin (FXN) gene's first intron (IGIBi016-A) and a non-FRDA healthy control individual (IGIBi017-A).
  4. Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.
  5. Enhancing healthy aging with small molecules: A mitochondrial perspective.
  6. The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study.
  7. Role of mitochondria in doxorubicin-mediated cardiotoxicity: from molecular mechanisms to therapeutic strategies.
  8. Mitochondria at the Nanoscale: Physics Meets Biology-What Does It Mean for Medicine?
  9. Genetic heterogeneity and respiratory chain enzyme analysis in pediatric Indian patients with mitochondrial disorder: Report of novel variants in POLG1 gene and their functional implication using molecular dynamic simulation.
  10. m6A RNA methylation regulates mitochondrial function.
  11. Activity-dependent mitochondrial ROS signaling regulates recruitment of glutamate receptors to synapses.
  12. Mitophagy defect mediates the aging-associated hallmarks in Hutchinson-Gilford progeria syndrome.
  13. Mitochondria: the gatekeepers between metabolism and immunity.
  14. DNM1L variant presenting as adolescent-onset sensory neuronopathy, spasticity, dystonia, and ataxia.
  15. Mitochondrial damage and clearance in retinal pigment epithelial cells.
  16. Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria.
  17. Fatty acid oxidation drives mitochondrial hydrogen peroxide production by α-ketoglutarate dehydrogenase.
  18. GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes.
  19. Hepatic mitochondrial reductive stress in the pathogenesis and treatment of steatotic liver disease.
  20. PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.
  21. Two distinct waves of transcriptome and translatome changes drive Drosophila germline stem cell differentiation.
  1. Nature. 2024 Mar 13.
    Mitochondrial complex I activity in microglia sustains neuroinflammation.
    L Peruzzotti-Jametti, C M Willis, G Krzak, R Hamel, L Pirvan, R-B Ionescu, J A Reisz, H A Prag, M E Garcia-Segura, V Wu, Y Xiang, B Barlas, A M Casey, A M R van den Bosch, A M Nicaise, L Roth, G R Bates, H Huang, P Prasad, A E Vincent, C Frezza, C Viscomi, G Balmus, Z Takats, J C Marioni, A D'Alessandro, M P Murphy, I Mohorianu, S Pluchino.
      Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.
    DOI:  https://doi.org/10.1038/s41586-024-07167-9
  2. Brain. 2024 Mar 13. pii: awae057. [Epub ahead of print]
    Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant.
    Beryll Blickhäuser, Sarah L Stenton, Christiane M Neuhofer, Elisa Floride, Victoria Nesbitt, Carl Fratter, Johannes Koch, Birgit Kauffmann, Claudia Catarino, Lea Dewi Schlieben, Robert Kopajtich, Valerio Carelli, Alfredo A Sadun, Robert McFarland, Fang Fang, Chiara La Morgia, Stéphanie Paquay, Marie Cécile Nassogne, Daniele Ghezzi, Costanza Lamperti, Saskia Wortmann, Jo Poulton, Thomas Klopstock, Holger Prokisch.
      Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterised by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA (mtDNA) genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mtDNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G>A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits.
    Keywords:  Leber hereditary optic neuropathy (LHON); Leigh syndrome spectrum (LSS); digenic inheritance; mitochondrial complex I (CI)
    DOI:  https://doi.org/10.1093/brain/awae057
  3. Stem Cell Res. 2024 Mar 11. pii: S1873-5061(24)00080-1. [Epub ahead of print]77 103382
    Generation and characterization of iPSC lines from Friedreich's ataxia patient (FRDA) with GAA.TTC repeat expansion in the Frataxin (FXN) gene's first intron (IGIBi016-A) and a non-FRDA healthy control individual (IGIBi017-A).
    Istaq Ahmad, Asangla Kamai, Sana Zahra, Himanshi Kapoor, Achal Kumar Srivastava, Mohammed Faruq.
      Friedreich's ataxia is a spinocerebellar degenerative disease caused by microsatellite (GAA.TTC)n repeat expansion in the first intron of FXN gene. Here, we developed iPSC lines from an FRDA patient (IGIBi016-A) and non-FRDA healthy control (IGIBi017-A). Both iPSC lines displayed typical iPSC morphology, expression of pluripotency markers, regular karyotypes (46, XY; 46, XX), capacity to grow into three germ layers, and FRDA hallmark -GAA repeat expansion and decreased FXN mRNA. Through these iPSC lines, FRDA phenotypes may be replicated in the in vitro assays, by creating neuron subtypes, cardiomyocytes and 3D organoids, for molecular and cellular biomarkers and therapeutic applications.
    DOI:  https://doi.org/10.1016/j.scr.2024.103382
  4. Cells. 2024 Feb 27. pii: 410. [Epub ahead of print]13(5):
    Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.
    Kuldeep Tripathi, Dorit Ben-Shachar.
      Mitochondria, the energy suppliers of the cells, play a central role in a variety of cellular processes essential for survival or leading to cell death. Consequently, mitochondrial dysfunction is implicated in numerous general and CNS disorders. The clinical manifestations of mitochondrial dysfunction include metabolic disorders, dysfunction of the immune system, tumorigenesis, and neuronal and behavioral abnormalities. In this review, we focus on the mitochondrial role in the CNS, which has unique characteristics and is therefore highly dependent on the mitochondria. First, we review the role of mitochondria in neuronal development, synaptogenesis, plasticity, and behavior as well as their adaptation to the intricate connections between the different cell types in the brain. Then, we review the sparse knowledge of the mechanisms of exogenous mitochondrial uptake and describe attempts to determine their half-life and transplantation long-term effects on neuronal sprouting, cellular proteome, and behavior. We further discuss the potential of mitochondrial transplantation to serve as a tool to study the causal link between mitochondria and neuronal activity and behavior. Next, we describe mitochondrial transplantation's therapeutic potential in various CNS disorders. Finally, we discuss the basic and reverse-translation challenges of this approach that currently hinder the clinical use of mitochondrial transplantation.
    Keywords:  CNS; mitochondria; mitochondria and behavior; mitochondrial transplantation; neural development and function; neuropsychiatric disorders
    DOI:  https://doi.org/10.3390/cells13050410
  5. Med Res Rev. 2024 Mar 14.
    Enhancing healthy aging with small molecules: A mitochondrial perspective.
    Xiujiao Qin, Hongyuan Li, Huiying Zhao, Le Fang, Xiaohui Wang.
      The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.
    Keywords:  aging; mitochondrial; mitophagy; redox homeostasis; unfolded protein response
    DOI:  https://doi.org/10.1002/med.22034
  6. Front Cell Dev Biol. 2024 ;12 1331351
    The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study.
    C Nogueira, C Pereira, L Silva, Mateus Laranjeira, A Lopes, R Neiva, E Rodrigues, T Campos, E Martins, A Bandeira, M Coelho, M Magalhães, J Damásio, A Gaspar, P Janeiro, A Levy Gomes, A C Ferreira, S Jacinto, J P Vieira, L Diogo, H Santos, C Mendonça, L Vilarinho.
      Introduction: Rare disorders that are genetically and clinically heterogeneous, such as mitochondrial diseases (MDs), have a challenging diagnosis. Nuclear genes codify most proteins involved in mitochondrial biogenesis, despite all mitochondria having their own DNA. The development of next-generation sequencing (NGS) technologies has revolutionized the understanding of many genes involved in the pathogenesis of MDs. In this new genetic era, using the NGS approach, we aimed to identify the genetic etiology for a suspected MD in a cohort of 450 Portuguese patients. Methods: We examined 450 patients using a combined NGS strategy, starting with the analysis of a targeted mitochondrial panel of 213 nuclear genes, and then proceeding to analyze the whole mitochondrial DNA. Results and Discussion: In this study, we identified disease-related variants in 134 (30%) analyzed patients, 88 with nuclear DNA (nDNA) and 46 with mitochondrial DNA (mtDNA) variants, most of them being pediatric patients (66%), of which 77% were identified in nDNA and 23% in mtDNA. The molecular analysis of this cohort revealed 72 already described pathogenic and 20 novel, probably pathogenic, variants, as well as 62 variants of unknown significance. For this cohort of patients with suspected MDs, the use of a customized gene panel provided a molecular diagnosis in a timely and cost-effective manner. Patients who cannot be diagnosed after this initial approach will be further selected for whole-exome sequencing. Conclusion: As a national laboratory for the study and research of MDs, we demonstrated the power of NGS to achieve a molecular etiology, expanding the mutational spectrum and proposing accurate genetic counseling in this group of heterogeneous diseases without therapeutic options.
    Keywords:  mitochondrial DNA; mitochondrial diseases; next-generation sequencing; nuclear DNA; nuclear genes; oxidative phosphorylation; respiratory chain
    DOI:  https://doi.org/10.3389/fcell.2024.1331351
  7. Cell Stress Chaperones. 2024 Mar 12. pii: S1355-8145(24)00056-7. [Epub ahead of print]
    Role of mitochondria in doxorubicin-mediated cardiotoxicity: from molecular mechanisms to therapeutic strategies.
    Tianen Wang, Guoli Xing, Tong Fu, Yanchun Ma, Qi Wang, Shuxiang Zhang, Xing Chang, Ying Tong.
      This comprehensive review delves into the pivotal role of mitochondria in doxorubicin-induced cardiotoxicity, a significant complication limiting the clinical use of this potent anthracycline chemotherapeutic agent. Doxorubicin, while effective against various malignancies, is associated with dose-dependent cardiotoxicity, potentially leading to irreversible cardiac damage. The review meticulously dissects the molecular mechanisms underpinning this cardiotoxicity, particularly focusing on mitochondrial dysfunction, a central player in this adverse effect. Central to the discussion is the concept of mitochondrial quality control (MQC), including mitochondrial dynamics (fusion/fission balance) and mitophagy. The review presents evidence linking aberrations in these processes to cardiotoxicity in doxorubicin-treated patients. It elucidates how doxorubicin disrupts mitochondrial dynamics, leading to an imbalance between mitochondrial fission and fusion, and impairs mitophagy, culminating in the accumulation of dysfunctional mitochondria and subsequent cardiac cell damage. Furthermore, the review explores emerging therapeutic strategies targeting mitochondrial dysfunction. It highlights the potential of modulating mitochondrial dynamics and enhancing mitophagy to mitigate doxorubicin-induced cardiac damage. These strategies include pharmacological interventions with mitochondrial fission inhibitors, fusion promoters, and agents that modulate mitophagy. The review underscores the promising results from preclinical studies while advocating for more extensive clinical trials to validate these approaches in human patients. In conclusion, this review offers valuable insights into the intricate relationship between mitochondrial dysfunction and doxorubicin-mediated cardiotoxicity. It underscores the need for continued research into targeted mitochondrial therapies as a means to improve the cardiac safety profile of doxorubicin, thereby enhancing the overall treatment outcomes for cancer patients.
    Keywords:  cardiotoxicity; doxorubicin; mitochondria; mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.cstres.2024.03.003
  8. Int J Mol Sci. 2024 Feb 29. pii: 2835. [Epub ahead of print]25(5):
    Mitochondria at the Nanoscale: Physics Meets Biology-What Does It Mean for Medicine?
    Lev Mourokh, Jonathan Friedman.
      Mitochondria are commonly perceived as "cellular power plants". Intriguingly, power conversion is not their only function. In the first part of this paper, we review the role of mitochondria in the evolution of eukaryotic organisms and in the regulation of the human body, specifically focusing on cancer and autism in relation to mitochondrial dysfunction. In the second part, we overview our previous works, revealing the physical principles of operation for proton-pumping complexes in the inner mitochondrial membrane. Our proposed simple models reveal the physical mechanisms of energy exchange. They can be further expanded to answer open questions about mitochondrial functions and the medical treatment of diseases associated with mitochondrial disorders.
    Keywords:  autism spectrum disorder; carcinogenesis; equations of motion; mitochondria; proton-pumping complex; respiratory transport chain
    DOI:  https://doi.org/10.3390/ijms25052835
  9. Mitochondrion. 2024 Mar 11. pii: S1567-7249(24)00028-X. [Epub ahead of print]76 101870
    Genetic heterogeneity and respiratory chain enzyme analysis in pediatric Indian patients with mitochondrial disorder: Report of novel variants in POLG1 gene and their functional implication using molecular dynamic simulation.
    Debolina Saha, Sonam Kothari, Shilpa Duttaprasanna Kulkarni, Menaka Thambiraja, Ragothaman M Yennamalli, Dhanjit K Das.
      Mitochondrial disorders are a heterogeneous group of disorders caused by mutations in the mitochondrial DNA or in nuclear genes encoding the mitochondrial proteins and subunits. Polymerase Gamma (POLG) is a nuclear gene and mutation in the POLG gene are one of the major causes of inherited mitochondrial disorders. In this study, 15 pediatric patients, with a wide spectrum of clinical phenotypes were screened using blood samples (n = 15) and muscle samples (n = 4). Respiratory chain enzyme analysis in the muscle samples revealed multi-complex deficiencies with Complex I deficiency present in (1/4) patients, Complex II (2/4), Complex III (3/4) and Complex IV (2/4) patients. Multiple large deletions were observed in 4/15 patients using LR-PCR. Whole exome sequencing (WES) revealed a compound heterozygous mutation consisting of a POLG1 novel variant (NP_002684.1:p.Trp261X) and a missense variant (NP_002684.1:p. Leu304Arg) in one patient and another patient harboring a novel homozygous POLG1 variant (NP_002684.1:p. Phe750Val). These variants (NP_002684.1:p. Leu304Arg) and (NP_002684.1:p. Phe750Val) and their interactions with DNA were modelled using molecular docking and molecular dynamics (MD) simulation studies. The protein conformation was analyzed as root mean square deviation (RMSD), root mean square fluctuation (RMSF) which showed local fluctuations in the mutants compared to the wildtype. However, Solvent Accessible Surface Area (SASA) significantly increased for NP_002684.1:p.Leu304Arg and decreased in NP_002684.1:p.Phe750Val mutants. Further, Contact Order analysis indicated that the Aromatic-sulfur interactions were destabilizing in the mutants. Overall, these in-silico analysis has revealed a destabilizing mutations suggesting pathogenic variants in POLG1 gene.
    Keywords:  Mitochondrial disorders; Molecular docking; POLG1; Respiratory chain enzyme analysis; Sanger sequencing
    DOI:  https://doi.org/10.1016/j.mito.2024.101870
  10. Hum Mol Genet. 2024 Mar 14. pii: ddae029. [Epub ahead of print]
    m6A RNA methylation regulates mitochondrial function.
    Michael Kahl, Zhaofa Xu, Saravanan Arumugam, Brittany Edens, Mariafausta Fischietti, Allen C Zhu, Leonidas C Platanias, Chuan He, Xiaoxi Zhuang, Yongchao C Ma.
      RNA methylation of N6-methyladenosine (m6A) is emerging as a fundamental regulator of every aspect of RNA biology. RNA methylation directly impacts protein production to achieve quick modulation of dynamic biological processes. However, whether RNA methylation regulates mitochondrial function is not known, especially in neuronal cells which require a high energy supply and quick reactive responses. Here we show that m6A RNA methylation regulates mitochondrial function through promoting nuclear-encoded mitochondrial complex subunit RNA translation. Conditional genetic knockout of m6A RNA methyltransferase Mettl14 (Methyltransferase like 14) by Nestin-Cre together with metabolomic analysis reveals that Mettl14 knockout-induced m6A depletion significantly downregulates metabolites related to energy metabolism. Furthermore, transcriptome-wide RNA methylation profiling of wild type and Mettl14 knockout mouse brains by m6A-Seq shows enrichment of methylation on mitochondria-related RNA. Importantly, loss of m6A leads to a significant reduction in mitochondrial respiratory capacity and membrane potential. These functional defects are paralleled by the reduced expression of mitochondrial electron transport chain complexes, as well as decreased mitochondrial super-complex assembly and activity. Mechanistically, m6A depletion decreases the translational efficiency of methylated RNA encoding mitochondrial complex subunits through reducing their association with polysomes, while not affecting RNA stability. Together, these findings reveal a novel role for RNA methylation in regulating mitochondrial function. Given that mitochondrial dysfunction and RNA methylation have been increasingly implicate in neurodegenerative disorders, our findings not only provide insights into fundamental mechanisms regulating mitochondrial function, but also open up new avenues for understanding the pathogenesis of neurological diseases.
    Keywords:  m6A RNA methylation; metabolomics; mitochondria; neurological disease; transcriptomics
    DOI:  https://doi.org/10.1093/hmg/ddae029
  11. Elife. 2024 Mar 14. pii: e92376. [Epub ahead of print]13
    Activity-dependent mitochondrial ROS signaling regulates recruitment of glutamate receptors to synapses.
    Rachel L Doser, Kaz M Knight, Ennis W Deihl, Frederic J Hoerndli.
      Our understanding of mitochondrial signaling in the nervous system has been limited by the technical challenge of analyzing mitochondrial function in vivo. In the transparent genetic model Caenorhabditis elegans, we were able to manipulate and measure mitochondrial ROS (reactive oxygen species) signaling of individual mitochondria as well as neuronal activity of single neurons in vivo. Using this approach, we provide evidence supporting a novel role for mitochondrial ROS signaling in dendrites of excitatory glutamatergic C. elegans interneurons. Specifically, we show that following neuronal activity, dendritic mitochondria take up calcium (Ca2+) via the mitochondrial Ca2+ uniporter MCU-1 that results in an upregulation of mitochondrial ROS production. We also observed that mitochondria are positioned in close proximity to synaptic clusters of GLR-1, the C. elegans ortholog of the AMPA subtype of glutamate receptors that mediate neuronal excitation. We show that synaptic recruitment of GLR-1 is upregulated when MCU-1 function is pharmacologically or genetically impaired but is downregulated by mitoROS signaling. Thus, signaling from postsynaptic mitochondria may regulate excitatory synapse function to maintain neuronal homeostasis by preventing excitotoxicity and energy depletion.
    Keywords:  C. elegans; cell biology; neuroscience
    DOI:  https://doi.org/10.7554/eLife.92376
  12. Aging Cell. 2024 Mar 14. e14143
    Mitophagy defect mediates the aging-associated hallmarks in Hutchinson-Gilford progeria syndrome.
    Yingying Sun, Le Xu, Yi Li, Shunze Jia, Gang Wang, Xufeng Cen, Yuyan Xu, Zhongkai Cao, Jingjing Wang, Ning Shen, Lidan Hu, Jin Zhang, Jianhua Mao, Hongguang Xia, Zhihong Liu, Xudong Fu.
      Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for aging. The cellular machinery mediating age-associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-associated phenotypes of HGPS-MSCs by inhibiting the STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI-77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging-associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging-associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.
    Keywords:  HGPS; UMI-77; aging; mitophagy
    DOI:  https://doi.org/10.1111/acel.14143
  13. Front Immunol. 2024 ;15 1334006
    Mitochondria: the gatekeepers between metabolism and immunity.
    Giovanna Trinchese, Fabiano Cimmino, Angela Catapano, Gina Cavaliere, Maria Pina Mollica.
      Metabolism and immunity are crucial monitors of the whole-body homeodynamics. All cells require energy to perform their basic functions. One of the most important metabolic skills of the cell is the ability to optimally adapt metabolism according to demand or availability, known as metabolic flexibility. The immune cells, first line of host defense that circulate in the body and migrate between tissues, need to function also in environments in which nutrients are not always available. The resilience of immune cells consists precisely in their high adaptive capacity, a challenge that arises especially in the framework of sustained immune responses. Pubmed and Scopus databases were consulted to construct the extensive background explored in this review, from the Kennedy and Lehninger studies on mitochondrial biochemistry of the 1950s to the most recent findings on immunometabolism. In detail, we first focus on how metabolic reconfiguration influences the action steps of the immune system and modulates immune cell fate and function. Then, we highlighted the evidence for considering mitochondria, besides conventional cellular energy suppliers, as the powerhouses of immunometabolism. Finally, we explored the main immunometabolic hubs in the organism emphasizing in them the reciprocal impact between metabolic and immune components in both physiological and pathological conditions.
    Keywords:  immunometabolism; metabolic flexibility; metabolic reprogramming; mitochondrial dynamics; mitochondrial function
    DOI:  https://doi.org/10.3389/fimmu.2024.1334006
  14. J Pediatr Neurol. 2023 Dec;21(6): 475-478
    DNM1L variant presenting as adolescent-onset sensory neuronopathy, spasticity, dystonia, and ataxia.
    Alexander S Wang, Gabrielle Lemire, Grace E VanNoy, Christina Austin-Tse, Anne O'Donnell-Luria, Camilla Kilbane.
      DMN1L encodes for dynamin-like protein 1 (DLP1) which plays a key role in perixosomal and mitochondrial fission. Individuals with heterozygous variants in DNM1L present with a wide range of neurologic symptoms, including encephalopathy, epilepsy, and motor deficits. Here we report on a woman presenting with adolescence onset of sensory neuronopathy, spasticity, dystonia, and ataxia. Trio genome sequencing identified a heterozygous variant in DNM1L (NM_012062.3 c.121G>A/p.Val41Met) which was thought to be pathogenic. This case describes the latest known symptomatic onset of DMN1L-related disease described in literature. We highlight our approach to a challenging diagnostic workup and interpretation of a specific variant that has not been previously reported. Furthermore, the case highlights the diagnostic importance of utilizing genomic sequencing and research studies for patients with rare disease.
    Keywords:  DLP1; DNM1L; ataxia; dystonia; mitochondrial; neuropathy; sensory neuronopathy; spasticity
    DOI:  https://doi.org/10.1055/s-0043-1771352
  15. Acta Ophthalmol. 2024 Mar;102 Suppl 282 3-53
    Mitochondrial damage and clearance in retinal pigment epithelial cells.
    Iswariyaraja Sridevi Gurubaran.
      Age-related macular degeneration (AMD) is a devastating eye disease that causes permanent vision loss in the central part of the retina, known as the macula. Patients with such severe visual loss face a reduced quality of life and are at a 1.5 times greater risk of death compared to the general population. Currently, there is no cure for or effective treatment for dry AMD. There are several mechanisms thought to underlie the disease, for example, ageing-associated chronic oxidative stress, mitochondrial damage, harmful protein aggregation and inflammation. As a way of gaining a better understanding of the molecular mechanisms behind AMD and thus developing new therapies, we have created a peroxisome proliferator-activated receptor gamma coactivator 1-alpha and nuclear factor erythroid 2-related factor 2 (PGC1α/NFE2L2) double-knockout (dKO) mouse model that mimics many of the clinical features of dry AMD, including elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen-like structures in retinal pigment epithelial cells (RPE). In addition, a human RPE cell-based model was established to examine the impact of non-functional intracellular clearance systems on inflammasome activation. In this study, we found that there was a disturbance in the autolysosomal machinery responsible for clearing mitochondria in the RPE cells of one-year-old PGC1α/NFE2L2-deficient mice. The confocal immunohistochemical analysis revealed an increase in autophagosome marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) as well as multiple mitophagy markers such as PTE-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN), along with signs of damaged mitochondria. However, no increase in autolysosome formation was detected, nor was there a colocalization of the lysosomal marker LAMP2 or the mitochondrial marker, ATP synthase β. There was an upregulation of late autolysosomal fusion Ras-related protein (Rab7) in the perinuclear space of RPE cells, together with autofluorescent aggregates. Additionally, we observed an increase in the numbers of Toll-like receptors 3 and 9, while those of NOD-like receptor 3 were decreased in PGC1α/NFE2L2 dKO retinal specimens compared to wild-type animals. There was a trend towards increased complement component C5a and increased involvement of the serine protease enzyme, thrombin, in enhancing the terminal pathway producing C5a, independent of C3. The levels of primary acute phase C-reactive protein and receptor for advanced glycation end products were also increased in the PGC1α/NFE2L2 dKO retina. Furthermore, selective proteasome inhibition with epoxomicin promoted both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondrial-mediated oxidative stress, leading to the release of mitochondrial DNA to the cytosol, resulting in potassium efflux-dependent activation of the absent in melanoma 2 (AIM2) inflammasome and the subsequent secretion of interleukin-1β in ARPE-19 cells. In conclusion, the data suggest that there is at least a relative decrease in mitophagy, increases in the amounts of C5 and thrombin and decreased C3 levels in this dry AMD-like model. Moreover, selective proteasome inhibition evoked mitochondrial damage and AIM2 inflammasome activation in ARPE-19 cells.
    Keywords:  ageing; inflammasomes; inflammation; macular degeneration; mitochondria; mitophagy; oxidative stress; protein aggregation; retinal pigment epithelium
    DOI:  https://doi.org/10.1111/aos.16661
  16. FEBS J. 2024 Mar 11.
    Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria.
    Sara Al Rawi, Lorna Simpson, Guðrún Agnarsdóttir, Neil Q McDonald, Veronika Chernuha, Orly Elpeleg, Massimo Zeviani, Roger A Barker, Ronen Spiegel, Heike Laman.
      Mutations in FBXO7 have been discovered to be associated with an atypical parkinsonism. We report here a new homozygous missense mutation in a paediatric patient that causes an L250P substitution in the dimerisation domain of Fbxo7. This alteration selectively ablates the Fbxo7-PI31 interaction and causes a significant reduction in Fbxo7 and PI31 levels in patient cells. Consistent with their association with proteasomes, patient fibroblasts have reduced proteasome activity and proteasome subunits. We also show PI31 interacts with the MiD49/51 fission adaptor proteins, and unexpectedly, PI31 acts to facilitate SCFFbxo7 -mediated ubiquitination of MiD49. The L250P mutation reduces the SCFFbxo7 ligase-mediated ubiquitination of a subset of its known substrates. Although MiD49/51 expression was reduced in patient cells, there was no effect on the mitochondrial network. However, patient cells show reduced levels of mitochondrial function and mitophagy, higher levels of ROS and are less viable under stress. Our study demonstrates that Fbxo7 and PI31 regulate proteasomes and mitochondria and reveals a new function for PI31 in enhancing the SCFFbxo7 E3 ubiquitin ligase activity.
    Keywords:  E3 ubiquitin ligase; Fbxo7/PARK15; Parkinson's disease; mitochondria; proteasome
    DOI:  https://doi.org/10.1111/febs.17114
  17. J Biol Chem. 2024 Mar 11. pii: S0021-9258(24)01654-5. [Epub ahead of print] 107159
    Fatty acid oxidation drives mitochondrial hydrogen peroxide production by α-ketoglutarate dehydrogenase.
    Cathryn Grayson, Ben Faerman, Olivia Koufos, Ryan J Mailloux.
      In the present study, we examined the mitochondrial hydrogen peroxide (mH2O2) generating capacity of α-ketoglutarate dehydrogenase (KGDH) and compared it to components of the electron transport chain (ETC) using liver mitochondria isolated from male and female C57BL6N mice. We show for the first time there are some sex dimorphisms in the production of mH2O2 by ETC complexes I and III when mitochondria are fueled with different substrates. However, in our investigations into these sex effects, we made the unexpected discovery that: 1. KGDH serves as a major mH2O2 supplier in male and female liver mitochondria and 2. KGDH can form mH2O2 when mitochondria are energized with fatty acids, but only when malate is used to prime the Krebs cycle. Surprisingly, 2-keto-3-methylvaleric acid (KMV), a site-specific inhibitor for KGDH, nearly abolished mH2O2 generation in both male and female liver mitochondria oxidizing palmitoyl-carnitine. KMV inhibited mH2O2 production in liver mitochondria from male and female mice oxidizing myristoyl-, octanoyl-, or butyryl-carnitine. S1QEL 1.1 (S1) and S3QEL 2 (S3), compounds that inhibit reactive oxygen species (ROS) generation by complexes I and III, respectively, without interfering with OxPhos, had a negligible effect on the rate of mH2O2 production when pyruvate or acyl-carnitines were used as fuels. However, inclusion of KMV in reaction mixtures containing S1 and/or S3 almost abolished mH2O2 generation. Together, our findings suggest KGDH is the main mH2O2 generator in liver mitochondria, even when fatty acids are used as fuel.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107159
  18. Cells. 2024 Mar 04. pii: 448. [Epub ahead of print]13(5):
    GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes.
    Qiang Zhu, Matthew E Combs, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.
      Cardiomyocytes rely on proper mitochondrial homeostasis to maintain contractility and achieve optimal cardiac performance. Mitochondrial homeostasis is controlled by mitochondrial fission, fusion, and mitochondrial autophagy (mitophagy). Mitophagy plays a particularly important role in promoting the degradation of dysfunctional mitochondria in terminally differentiated cells. However, the precise mechanisms by which this is achieved in cardiomyocytes remain opaque. Our study identifies GRAF1 as an important mediator in PINK1-Parkin pathway-dependent mitophagy. Depletion of GRAF1 (Arhgap26) in cardiomyocytes results in actin remodeling defects, suboptimal mitochondria clustering, and clearance. Mechanistically, GRAF1 promotes Parkin-LC3 complex formation and directs autophagosomes to damaged mitochondria. Herein, we found that these functions are regulated, at least in part, by the direct binding of GRAF1 to phosphoinositides (PI(3)P, PI(4)P, and PI(5)P) on autophagosomes. In addition, PINK1-dependent phosphorylation of Parkin promotes Parkin-GRAF1-LC3 complex formation, and PINK1-dependent phosphorylation of GRAF1 (on S668 and S671) facilitates the clustering and clearance of mitochondria. Herein, we developed new phosphor-specific antibodies to these sites and showed that these post-translational modifications are differentially modified in human hypertrophic cardiomyopathy and dilated cardiomyopathy. Furthermore, our metabolic studies using serum collected from isoproterenol-treated WT and GRAF1CKO mice revealed defects in mitophagy-dependent cardiomyocyte fuel flexibility that have widespread impacts on systemic metabolism. In summary, our study reveals that GRAF1 co-regulates actin and membrane dynamics to promote cardiomyocyte mitophagy and that dysregulation of GRAF1 post-translational modifications may underlie cardiac disease pathogenesis.
    Keywords:  GRAF1; PINK1-Parkin pathway; cardiomyocytes; metabolism; mitophagy
    DOI:  https://doi.org/10.3390/cells13050448
  19. Trends Pharmacol Sci. 2024 Mar 11. pii: S0165-6147(24)00030-0. [Epub ahead of print]
    Hepatic mitochondrial reductive stress in the pathogenesis and treatment of steatotic liver disease.
    Mari J Jokinen, Panu K Luukkonen.
      Steatotic liver diseases (SLDs) affect one-third of the population, but the pathogenesis underlying these diseases is not well understood, limiting the available treatments. A common factor in SLDs is increased hepatic mitochondrial reductive stress, which occurs as a result of excessive lipid and alcohol metabolism. Recent research has also shown that genetic risk factors contribute to this stress. This review aims to explore how these risk factors increase hepatic mitochondrial reductive stress and how it disrupts hepatic metabolism, leading to SLDs. Additionally, the review will discuss the latest clinical studies on pharmaceutical treatments for SLDs, specifically peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor (THR) agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers. These treatments have a common effect of decreasing hepatic mitochondrial reductive stress, which has been largely overlooked.
    Keywords:  NAD(+); NADH; alcohol-associated liver disease; fibrosis; metabolic dysfunction-associated steatotic liver disease; redox
    DOI:  https://doi.org/10.1016/j.tips.2024.02.003
  20. EMBO Rep. 2024 Mar 13.
    PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.
    Cheng Chen, Qianyu Liu, Wenjie Chen, Zhiyuan Gong, Bo Kang, Meihua Sui, Liming Huang, Ying-Jie Wang.
      Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.
    Keywords:  Electron Transport Chain Complex; Human Naive Pluripotency; PRODH; Reactive Oxygen Species; mtOXPHOS
    DOI:  https://doi.org/10.1038/s44319-024-00110-z
  21. EMBO J. 2024 Mar 13.
    Two distinct waves of transcriptome and translatome changes drive Drosophila germline stem cell differentiation.
    Tamsin J Samuels, Jinghua Gui, Daniel Gebert, Felipe Karam Teixeira.
      The tight control of fate transitions during stem cell differentiation is essential for proper tissue development and maintenance. However, the challenges in studying sparsely distributed adult stem cells in a systematic manner have hindered efforts to identify how the multilayered regulation of gene expression programs orchestrates stem cell differentiation in vivo. Here, we synchronised Drosophila female germline stem cell (GSC) differentiation in vivo to perform in-depth transcriptome and translatome analyses at high temporal resolution. This characterisation revealed widespread and dynamic changes in mRNA level, promoter usage, exon inclusion, and translation efficiency. Transient expression of the master regulator, Bam, drives a first wave of expression changes, primarily modifying the cell cycle program. Surprisingly, as Bam levels recede, differentiating cells return to a remarkably stem cell-like transcription and translation program, with a few crucial changes feeding into a second phase driving terminal differentiation to form the oocyte. Altogether, these findings reveal that rather than a unidirectional accumulation of changes, the in vivo differentiation of stem cells relies on distinctly regulated and developmentally sequential waves.
    Keywords:  Differentiation; Drosophila; Germline; Transcription; Translation
    DOI:  https://doi.org/10.1038/s44318-024-00070-z
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