bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–03–19
thirty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.
  2. Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.
  3. Omics-based approaches for the systematic profiling of mitochondrial biology.
  4. Genetic Aberration Analysis of Mitochondrial Respiratory Complex I Implications in the Development of Neurological Disorders and Their Clinical Significance.
  5. Highly-purified rapidly expanding clones, RECs, are superior for functional-mitochondrial transfer.
  6. Role of amino acid metabolism in mitochondrial homeostasis.
  7. Effects of adverse fertility-related factors on mitochondrial DNA in the oocyte: a comprehensive review.
  8. Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis.
  9. Genetic modifiers modulate phenotypic expression of tafazzin deficiency in a mouse model of Barth syndrome.
  10. Pptc7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
  11. Restoration of mitochondrial function through activation of hypomodified tRNAs with pathogenic mutations associated with mitochondrial diseases.
  12. Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.
  13. Pharmacological Progress of Mitophagy Regulation.
  14. Fine-tune TMEM11 to unleash basal mitophagy.
  15. A novel approach to measure complex V ATP hydrolysis in frozen cell lysates and tissue homogenates.
  16. NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury.
  17. Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
  18. Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
  19. Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.
  20. Metabolic sensing and control in mitochondria.
  21. High-content assay to measure mitochondrial function and bacterial vacuole size in infected human primary macrophages.
  22. A Novel Metric for Predicting Severity of Disease Features in Friedreich's Ataxia.
  23. Mitochondrial protein transport: Versatility of translocases and mechanisms.
  24. Scale for the Assessment and Rating of Ataxia (SARA): Development of a Training Tool and Certification Program.
  25. FGF19 increases mitochondrial biogenesis and fusion in chondrocytes via the AMPKα-p38/MAPK pathway.
  26. A comprehensive perspective of Huntington's disease and mitochondrial dysfunction.
  27. SnapShot: Mitochondrial signaling.
  28. The Italian reappraisal on the most frequent genetic defects in hereditary optic neuropathies and the global top 10.
  29. Spatial mapping of mitochondrial networks and bioenergetics in lung cancer.
  30. Role of VPS39, a key tethering protein for endolysosomal trafficking and mitochondria-lysosome crosstalk, in health and disease.
  31. Exploring the role of mitochondria transfer/transplant and their long-non-coding RNAs in regenerative therapies for skin aging.
  32. 4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis.
  33. Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.
  34. DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity.
  35. Diversity of mitochondrial networks in lung cancer imaged.
  36. Mitophagy in ototoxicity.
  1. Proc Natl Acad Sci U S A. 2023 Mar 21. 120(12): e2207471120
    OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.
    Benjamín Cartes-Saavedra, Daniel Lagos, Josefa Macuada, Duxan Arancibia, Florence Burté, Marcela K Sjöberg-Herrera, María Estela Andrés, Rita Horvath, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner.
      Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from OPA1 GTPase (c.870+5G>A and c.889C>T) and GED (c.2713C>T and c.2818+5G>A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.
    Keywords:  ADOA; OPA1; cristae; dynamics; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2207471120
  2. EMBO Rep. 2023 Mar 17. e56114
    Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.
    Reut Hazan Ben-Menachem, Dvora Lintzer, Tamar Ziv, Koyeli Das, Irit Rosenhek-Goldian, Ziv Porat, Hila Ben Ami Pilo, Sharon Karniely, Ann Saada, Neta Regev-Rudzki, Ophry Pines.
      Vesicular transport is a means of communication. While cells can communicate with each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here, we show that functional mitochondria isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We isolate these mitochondrial-derived vesicles (MDVs) and find that they are relatively uniform in size, of about 100 nm, and carry selective protein cargo enriched for ATP synthase subunits. Remarkably, we further find that these MDVs harbor a functional ATP synthase complex. We demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP-producing vesicles, which can potentially regenerate ATP-deficient mitochondria and may participate in organelle-to-organelle communication.
    Keywords:  ATP synthase; membrane potential; mitochondria; mitochondrial-derived vesicles; protein distribution
    DOI:  https://doi.org/10.15252/embr.202256114
  3. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00118-1. [Epub ahead of print]83(6): 911-926
    Omics-based approaches for the systematic profiling of mitochondrial biology.
    Jasmin Adriana Schäfer, F X Reymond Sutandy, Christian Münch.
      Mitochondria are essential for cellular functions such as metabolism and apoptosis. They dynamically adapt to the changing environmental demands by adjusting their protein, nucleic acid, metabolite, and lipid contents. In addition, the mitochondrial components are modulated on different levels in response to changes, including abundance, activity, and interaction. A wide range of omics-based approaches has been developed to be able to explore mitochondrial adaptation and how mitochondrial function is compromised in disease contexts. Here, we provide an overview of the omics methods that allow us to systematically investigate the different aspects of mitochondrial biology. In addition, we show examples of how these methods have provided new biological insights. The emerging use of these toolboxes provides a more comprehensive understanding of the processes underlying mitochondrial function.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.015
  4. Ageing Res Rev. 2023 Mar 09. pii: S1568-1637(23)00065-X. [Epub ahead of print] 101906
    Genetic Aberration Analysis of Mitochondrial Respiratory Complex I Implications in the Development of Neurological Disorders and Their Clinical Significance.
    Ghulam Mehdi Dar, Ejaj Ahmad, Asgar Ali, Bhawna Mahajan, Ghulam Md Ashraf, Sundeep Singh Saluja.
      Growing neurological diseases pose difficult challenges for modern medicine to diagnose and manage them effectively. Many neurological disorders mainly occur due to genetic alteration in genes encoding mitochondrial proteins. Moreover, mitochondrial genes exhibit a higher rate of mutation due to the generation of Reactive oxygen species (ROS) during oxidative phosphorylation operating in their vicinity. Among the different complexes of Electron transport chain (ETC), NADH: Ubiquinone oxidoreductase (Mitochondrial complex I) is the most important. This multimeric enzyme, composed of 44 subunits, is encoded by both nuclear and mitochondrial genes. It often exhibits mutations resulting in development of various neurological diseases. The most prominent diseases include leigh syndrome (LS), leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy associated with ragged-red fibers (MERRF), idiopathic Parkinson's disease (PD) and, Alzheimer's disease (AD). Preliminary data suggest that mitochondrial complex I subunit genes mutated are frequently of nuclear origin; however, most of the mtDNA gene encoding subunits are also primarily involved. In this review, we have discussed the genetic origins of neurological disorders involving mitochondrial complex I and signified recent approaches to unravel the diagnostic and therapeutic potentials and their management.
    Keywords:  Complex I; Electron Transport Chain (ETC); Mitochondrial DNA (mtDNA); Neurological disorders; Oxidative Phosphorylation
    DOI:  https://doi.org/10.1016/j.arr.2023.101906
  5. Stem Cell Res Ther. 2023 Mar 16. 14(1): 40
    Highly-purified rapidly expanding clones, RECs, are superior for functional-mitochondrial transfer.
    Jiahao Yang, Lu Liu, Yasuaki Oda, Keisuke Wada, Mako Ago, Shinichiro Matsuda, Miho Hattori, Tsukimi Goto, Yuki Kawashima, Yumi Matsuzaki, Takeshi Taketani.
       BACKGROUND: Mitochondrial dysfunction caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA, which codes for mitochondrial components, are known to be associated with various genetic and congenital disorders. These mitochondrial disorders not only impair energy production but also affect mitochondrial functions and have no effective treatment. Mesenchymal stem cells (MSCs) are known to migrate to damaged sites and carry out mitochondrial transfer. MSCs grown using conventional culture methods exhibit heterogeneous cellular characteristics. In contrast, highly purified MSCs, namely the rapidly expanding clones (RECs) isolated by single-cell sorting, display uniform MSCs functionality. Therefore, we examined the differences between RECs and MSCs to assess the efficacy of mitochondrial transfer.
    METHODS: We established mitochondria-deficient cell lines (ρ0 A549 and ρ0 HeLa cell lines) using ethidium bromide. Mitochondrial transfer from RECs/MSCs to ρ0 cells was confirmed by PCR and flow cytometry analysis. We examined several mitochondrial functions including ATP, reactive oxygen species, mitochondrial membrane potential, and oxygen consumption rate (OCR). The route of mitochondrial transfer was identified using inhibition assays for microtubules/tunneling nanotubes, gap junctions, or microvesicles using transwell assay and molecular inhibitors.
    RESULTS: Co-culture of ρ0 cells with MSCs or RECs led to restoration of the mtDNA content. RECs transferred more mitochondria to ρ0 cells compared to that by MSCs. The recovery of mitochondrial function, including ATP, OCR, mitochondrial membrane potential, and mitochondrial swelling in ρ0 cells co-cultured with RECs was superior than that in cells co-cultured with MSCs. Inhibition assays for each pathway revealed that RECs were sensitive to endocytosis inhibitor, dynasore.
    CONCLUSIONS: RECs might serve as a potential therapeutic strategy for diseases linked to mitochondrial dysfunction by donating healthy mitochondria.
    Keywords:  Mesenchymal stem cells (MSCs); Mitochondrial dysfunction; Mitochondrial transfer; Rapidly expanding clones (RECs)
    DOI:  https://doi.org/10.1186/s13287-023-03274-y
  6. Front Cell Dev Biol. 2023 ;11 1127618
    Role of amino acid metabolism in mitochondrial homeostasis.
    Qiaochu Li, Thorsten Hoppe.
      Mitochondria are central hubs for energy production, metabolism and cellular signal transduction in eukaryotic cells. Maintenance of mitochondrial homeostasis is important for cellular function and survival. In particular, cellular metabolic state is in constant communication with mitochondrial homeostasis. One of the most important metabolic processes that provide energy in the cell is amino acid metabolism. Almost all of the 20 amino acids that serve as the building blocks of proteins are produced or degraded in the mitochondria. The synthesis of the amino acids aspartate and arginine depends on the activity of the respiratory chain, which is essential for cell proliferation. The degradation of branched-chain amino acids mainly occurs in the mitochondrial matrix, contributing to energy metabolism, mitochondrial biogenesis, as well as protein quality control in both mitochondria and cytosol. Dietary supplementation or restriction of amino acids in worms, flies and mice modulates lifespan and health, which has been associated with changes in mitochondrial biogenesis, antioxidant response, as well as the activity of tricarboxylic acid cycle and respiratory chain. Consequently, impaired amino acid metabolism has been associated with both primary mitochondrial diseases and diseases with mitochondrial dysfunction such as cancer. Here, we present recent observations on the crosstalk between amino acid metabolism and mitochondrial homeostasis, summarise the underlying molecular mechanisms to date, and discuss their role in cellular functions and organismal physiology.
    Keywords:  TCA cycle; amino acid metabolism; amino acid recycling; lifespan; mitochondrial homeostasis; proteasome; respiratory chain
    DOI:  https://doi.org/10.3389/fcell.2023.1127618
  7. Reprod Biol Endocrinol. 2023 Mar 17. 21(1): 27
    Effects of adverse fertility-related factors on mitochondrial DNA in the oocyte: a comprehensive review.
    Wenying Zhang, Fuju Wu.
      The decline of oocyte quality has profound impacts on fertilization, implantation, embryonic development, and the genetic quality of future generations. One factor that is often ignored but is involved in the decline of oocyte quality is mitochondrial DNA (mtDNA) abnormalities. Abnormalities in mtDNA affect the energy production of mitochondria, the dynamic balance of the mitochondrial network, and the pathogenesis of mtDNA diseases in offspring. In this review, we have detailed the characteristics of mtDNA in oocytes and the maternal inheritance of mtDNA. Next, we summarized the mtDNA abnormalities in oocytes derived from aging, diabetes, obesity, and assisted reproductive technology (ART) in an attempt to further elucidate the possible mechanisms underlying the decline in oocyte health. Because multiple infertility factors are often involved when an individual is infertile, a comprehensive understanding of the individual effects of each infertility-related factor on mtDNA is necessary. Herein, we consider the influence of infertility-related factors on the mtDNA of the oocyte as a collective perspective for the first time, providing a supplementary angle and reference for multi-directional improvement strategies of oocyte quality in the future. In addition, we highlight the importance of studying ART-derived mitochondrial abnormalities during every ART procedure.
    Keywords:  Aging; Assisted reproductive technology; Diabetes; Mitochondria; Obesity; Reproduction; mtDNA
    DOI:  https://doi.org/10.1186/s12958-023-01078-6
  8. Sci Rep. 2023 Mar 14. 13(1): 4193
    Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis.
    Teng-Hui Wu, Jing Peng, Li Yang, Yan-Hui Chen, Xiu-Lan Lu, Jiao-Tian Huang, Jie-Yu You, Wen-Xian Ou-Yang, Yue-Yu Sun, Yi-Nan Xue, Xiao Mao, Hui-Ming Yan, Rong-Na Ren, Jing Xie, Zhi-Heng Chen, Victor-Wei Zhang, Gui-Zhen Lyu, Fang He.
      Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged < 18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as "unlikely to have mitochondrial disorder". Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as "probably having mitochondrial disorder". Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.
    DOI:  https://doi.org/10.1038/s41598-023-31134-5
  9. Hum Mol Genet. 2023 Mar 14. pii: ddad041. [Epub ahead of print]
    Genetic modifiers modulate phenotypic expression of tafazzin deficiency in a mouse model of Barth syndrome.
    Suya Wang, Erika Yazawa, Erin Keating, Neil Mazumdar, Alexander Hauschild, Qing Ma, Haiyan Wu, Yang Xu, Xu Shi, Douglas Strathdee, Robert E Gerszten, Michael Schlame, William T Pu.
      Barth syndrome is an X-linked disorder caused by loss-of-function mutations in Tafazzin (TAZ), an acyltransferase that catalyzes remodeling of cardiolipin, a signature phospholipid of the inner mitochondrial membrane. Patients develop cardiac and skeletal muscle weakness, growth delay, and neutropenia, although phenotypic expression varies considerably between patients. Taz knockout mice recapitulate many of the hallmark features of the disease. We used mouse genetics to test the hypothesis that genetic modifiers alter the phenotypic manifestations of Taz inactivation. We crossed TazKO/X females in the C57BL6/J inbred strain to males from 8 inbred strains and evaluated the phenotypes of first generation (F1) TazKO/Y progeny, compared to TazWT/Y littermates. We observed that genetic background strongly impacted phenotypic expression. C57BL6/J and CAST/EiJ[F1] TazKO/Y mice developed severe cardiomyopathy, whereas A/J[F1] TazKO/Y mice had normal heart function. C57BL6/J and WSB/EiJ[F1] TazKO/Y mice had severely reduced treadmill endurance, whereas endurance was normal in A/J[F1] and CAST/EiJ[F1] TazKO/Y mice. In all genetic backgrounds, cardiolipin showed similar abnormalities in knockout mice, and transcriptomic and metabolomic investigations identified signatures of mitochondrial uncoupling and activation of the integrated stress response. TazKO/Y cardiac mitochondria were small, clustered, and had reduced cristae density in knockouts in severely affected genetic backgrounds but were relatively preserved in the permissive A/J[F1] strain. Gene expression and mitophagy measurements were consistent with reduced mitophagy in knockout mice in genetic backgrounds intolerant of Taz mutation. Our data demonstrate that genetic modifiers powerfully modulate phenotypic expression of Taz loss-of-function and act downstream of cardiolipin, possibly by altering mitochondrial quality control.
    DOI:  https://doi.org/10.1093/hmg/ddad041
  10. bioRxiv. 2023 Mar 01. pii: 2023.02.28.530351. [Epub ahead of print]
    Pptc7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
    Natalie M Niemi, Lia R Serrano, Laura K Muehlbauer, Catie Balnis, Keri-Lyn Kozul, Edrees H Rashan, Evgenia Shishkova, Kathryn L Schueler, Mark P Keller, Alan D Attie, Julia Pagan, Joshua J Coon, David J Pagliarini.
      Pptc7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass concomitant with elevation of the mitophagy receptors Bnip3 and Nix. Consistently, Pptc7 -/- mouse embryonic fibroblasts (MEFs) exhibit a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFsâ€" including multiple sites on Bnip3 and Nix. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that Pptc7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for Pptc7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
    DOI:  https://doi.org/10.1101/2023.02.28.530351
  11. Nucleic Acids Res. 2023 Mar 17. pii: gkad139. [Epub ahead of print]
    Restoration of mitochondrial function through activation of hypomodified tRNAs with pathogenic mutations associated with mitochondrial diseases.
    Ena Tomoda, Asuteka Nagao, Yuki Shirai, Kana Asano, Takeo Suzuki, Brendan J Battersby, Tsutomu Suzuki.
      Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged red fibers (MERRF) are major clinical subgroups of mitochondrial diseases caused by pathogenic point mutations in tRNA genes encoded in mtDNA. We previously reported a severe reduction in the frequency of 5-taurinomethyluridine (τm5U) and its 2-thiouridine derivative (τm5s2U) in the anticodons of mutant mt-tRNAs isolated from the cells of patients with MELAS and MERRF, respectively. The hypomodified tRNAs fail to decode cognate codons efficiently, resulting in defective translation of respiratory chain proteins in mitochondria. To restore the mitochondrial activity of MELAS patient cells, we overexpressed MTO1, a τm5U-modifying enzyme, in patient-derived myoblasts. We used a newly developed primer extension method and showed that MTO1 overexpression almost completely restored the τm5U modification of the MELAS mutant mt-tRNALeu(UUR). An increase in mitochondrial protein synthesis and oxygen consumption rate suggested that the mitochondrial function of MELAS patient cells can be activated by restoring the τm5U of the mutant tRNA. In addition, we confirmed that MTO1 expression restored the τm5s2U of the mutant mt-tRNALys in MERRF patient cells. These findings pave the way for epitranscriptomic therapies for mitochondrial diseases.
    DOI:  https://doi.org/10.1093/nar/gkad139
  12. EMBO J. 2023 Mar 14. e111901
    Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.
    Jennifer Ngo, Dong Wook Choi, Illana A Stanley, Linsey Stiles, Anthony J A Molina, Pei-Hsuan Chen, Ana Lako, Isabelle Chiao Han Sung, Rishov Goswami, Min-Young Kim, Nathanael Miller, Siyouneh Baghdasarian, Doyeon Kim-Vasquez, Anthony E Jones, Brett Roach, Vincent Gutierrez, Karel Erion, Ajit S Divakaruni, Marc Liesa, Nika N Danial, Orian S Shirihai.
      Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.
    Keywords:  CPT1; fatty acid oxidation; fission; fusion; mitochondrial dynamics
    DOI:  https://doi.org/10.15252/embj.2022111901
  13. Curr Neuropharmacol. 2023 Mar 14.
    Pharmacological Progress of Mitophagy Regulation.
    Sheikh Arslan Sehgal, Hao Wu, Muhammad Sajid, Summar Sohail, Muhammad Ahsan, Gulnaz Parveen, Mehreen Riaz, Muhammad Saleem Khan, Muhammad Nasir Iqbal, Abbeha Malik.
      With the advancement in novel drug discovery, biologically active compounds are considered pharmacological tools to understand complex biological mechanisms and the identification of potent therapeutic agents. Mitochondria boast a central role in different integral biological processes and mitochondrial dysfunction is associated with multiple pathologies. It is, therefore, prudent to target mitochondrial quality control mechanisms by using pharmacological approaches. However, there is a scarcity of biologically active molecules, which can interact with mitochondria directly. Currently, the chemical compounds used to induce mitophagy include oligomycin and antimycin A for impaired respiration and acute dissipation of mitochondrial membrane potential by using CCCP/FCCP, the mitochondrial uncouplers. These chemical probes alter the homeostasis of the mitochondria and limit our understanding of the energy regulatory mechanisms. Efforts are underway to find molecules that can bring about selective removal of defective mitochondria without compromising normal mitochondrial respiration. In this report, we have tried to summarize and status of the recently reported modulators of mitophagy.
    Keywords:  Mitophagy; mitochondria; mitochondrial quality control.; neurological disorders; pharmacology; power management system
    DOI:  https://doi.org/10.2174/1570159X21666230314140528
  14. J Cell Biol. 2023 Apr 03. pii: e202302118. [Epub ahead of print]222(4):
    Fine-tune TMEM11 to unleash basal mitophagy.
    Thomas G McWilliams.
      When mitochondrial damage threatens to disrupt cell and tissue homeostasis, selective autophagy (mitophagy) provides an important route to neutralize dysfunctional organelles. Whilst we understand much about stress-induced mitophagy, steady-state and spatial mechanisms remain elusive. In this issue, Gok et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202204021) reveal an unexpected role for TMEM11 in mitophagy regulation.
    DOI:  https://doi.org/10.1083/jcb.202302118
  15. Life Sci Alliance. 2023 Apr;pii: e202201628. [Epub ahead of print]6(4):
    A novel approach to measure complex V ATP hydrolysis in frozen cell lysates and tissue homogenates.
    Lucia Fernandez-Del-Rio, Cristiane Benincá, Frankie Villalobos, Cynthia Shu, Linsey Stiles, Marc Liesa, Ajit S Divakaruni, Rebeca Acin-Perez, Orian S Shirihai.
      Mitochondrial depolarization can initiate reversal activity of ATP synthase, depleting ATP by its hydrolysis. We have recently shown that increased ATP hydrolysis contributes to ATP depletion leading to a maladaptation in mitochondrial disorders, where maximal hydrolytic capacity per CV content is increasing. However, despite its importance, ATP hydrolysis is not a commonly studied parameter because of the limitations of the currently available methods. Methods that measure CV hydrolytic activity indirectly require the isolation of mitochondria and involve the introduction of detergents, preventing their utilization in clinical studies or any high-throughput analyses. Here, we describe a novel approach to assess maximal ATP hydrolytic capacity and maximal respiratory capacity in a single assay in cell lysates, PBMCs, and tissue homogenates that were previously frozen. The methodology described here has the potential to be used in clinical samples to determine adaptive and maladaptive adjustments of CV function in diseases, with the added benefit of being able to use frozen samples in a high-throughput manner and to explore ATP hydrolysis as a drug target for disease treatment.
    DOI:  https://doi.org/10.26508/lsa.202201628
  16. Nat Metab. 2023 Mar 13.
    NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury.
    Tomohito Doke, Sarmistha Mukherjee, Dhanunjay Mukhi, Poonam Dhillon, Amin Abedini, James G Davis, Karthikeyani Chellappa, Beishan Chen, Joseph A Baur, Katalin Susztak.
      Our understanding of how global changes in cellular metabolism contribute to human kidney disease remains incompletely understood. Here we show that nicotinamide adenine dinucleotide (NAD+) deficiency drives mitochondrial dysfunction causing inflammation and kidney disease development. Using unbiased global metabolomics in healthy and diseased human kidneys, we identify NAD+ deficiency as a disease signature. Furthermore using models of cisplatin- or ischaemia-reperfusion induced kidney injury in male mice we observed NAD+ depletion Supplemental nicotinamide riboside or nicotinamide mononucleotide restores NAD+ levels and improved kidney function. We find that cisplatin exposure causes cytosolic leakage of mitochondrial RNA (mtRNA) and activation of the cytosolic pattern recognition receptor retinoic acid-inducible gene I (RIG-I), both of which can be ameliorated by restoring NAD+. Male mice with RIG-I knock-out (KO) are protected from cisplatin-induced kidney disease. In summary, we demonstrate that the cytosolic release of mtRNA and RIG-I activation is an NAD+-sensitive mechanism contributing to kidney disease.
    DOI:  https://doi.org/10.1038/s42255-023-00761-7
  17. Res Sq. 2023 Feb 27. pii: rs.3.rs-2612547. [Epub ahead of print]
    Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
    Emily Warren, Eliza M Gordon-Lipkin, Foo Cheung, Jinguo Chen, Amrita Mukherjee, Richard Apps, John S Tsang, Jillian Jetmore, Shannon Kruk, Yuanjiu Lei, A Phillip West, Peter J McGuire.
      Background: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyperresponsiveness to pathogens and neurodegeneration. Methods: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. Results: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. Conclusions: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.21203/rs.3.rs-2612547/v1
  18. EMBO J. 2023 Mar 13. e111699
    Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
    Rebeca Acin-Perez, Cristiane Benincá, Lucia Fernandez Del Rio, Cynthia Shu, Siyouneh Baghdasarian, Vanessa Zanette, Christoph Gerle, Chimari Jiko, Ramzi Khairallah, Shaharyar Khan, David Rincon Fernandez Pacheco, Byourak Shabane, Karel Erion, Ruchi Masand, Sundeep Dugar, Cristina Ghenoiu, George Schreiner, Linsey Stiles, Marc Liesa, Orian S Shirihai.
      The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV.
    Keywords:  ATP hydrolysis; ATPase Inhibitor (ATPIF1); Complex V; epicatechin; muscular dystrophy
    DOI:  https://doi.org/10.15252/embj.2022111699
  19. Neuron. 2023 Mar 03. pii: S0896-6273(23)00123-X. [Epub ahead of print]
    Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.
    Dylan V Neel, Himanish Basu, Georgia Gunner, Matthew D Bergstresser, Richard M Giadone, Haeji Chung, Rui Miao, Vicky Chou, Eliza Brody, Xin Jiang, Edward Lee, Michelle E Watts, Christine Marques, Aaron Held, Brian Wainger, Clotilde Lagier-Tourenne, Yong-Jie Zhang, Leonard Petrucelli, Tracey L Young-Pearse, Alice S Chen-Plotkin, Lee L Rubin, Judy Lieberman, Isaac M Chiu.
      Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration.
    Keywords:  ALS; FTD; axon degeneration; cell death; gasdermins; innate immunity; mitochondria; neurodegeneration; neuroimmunology; pyroptosis
    DOI:  https://doi.org/10.1016/j.neuron.2023.02.019
  20. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00119-3. [Epub ahead of print]83(6): 877-889
    Metabolic sensing and control in mitochondria.
    Yuyang Liu, Kıvanç Birsoy.
      Mitochondria are membrane-enclosed organelles with endosymbiotic origins, harboring independent genomes and a unique biochemical reaction network. To perform their critical functions, mitochondria must maintain a distinct biochemical environment and coordinate with the cytosolic metabolic networks of the host cell. This coordination requires them to sense and control metabolites and respond to metabolic stresses. Indeed, mitochondria adopt feedback or feedforward control strategies to restrain metabolic toxicity, enable metabolic conservation, ensure stable levels of key metabolites, allow metabolic plasticity, and prevent futile cycles. A diverse panel of metabolic sensors mediates these regulatory circuits whose malfunctioning leads to inborn errors of metabolism with mild to severe clinical manifestations. In this review, we discuss the logic and molecular basis of metabolic sensing and control in mitochondria. The past research outlined recurring patterns in mitochondrial metabolic sensing and control and highlighted key knowledge gaps in this organelle that are potentially addressable with emerging technological breakthroughs.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.016
  21. STAR Protoc. 2023 Mar 17. pii: S2666-1667(23)00133-8. [Epub ahead of print]4(2): 102175
    High-content assay to measure mitochondrial function and bacterial vacuole size in infected human primary macrophages.
    Mariatou Dramé, Francisco Javier Garcia-Rodriguez, Carmen Buchrieser, Pedro Escoll.
      Regulation of bioenergetics and cell death are pivotal mitochondrial functions determining the responses of macrophages to infection. Here, we provide a protocol to investigate mitochondrial functions during infection of macrophages by intracellular bacteria. We describe steps for quantifying mitochondrial polarization, cell death, and bacterial infection in infected, living, human primary macrophages at the single-cell level. We also detail the use of the pathogen Legionella pneumophila as model. This protocol can be adapted to investigate mitochondrial functions in other settings. For complete details on the use and execution of this protocol, please refer to Escoll et al. (2021).1.
    Keywords:  Cell Biology; Cell-based Assays; High-throughput Screening; Immunology; Metabolism; Microbiology; Microscopy; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2023.102175
  22. Mov Disord. 2023 Mar 16.
    A Novel Metric for Predicting Severity of Disease Features in Friedreich's Ataxia.
    Layne N Rodden, Christian Rummey, Sudha Kessler, Robert B Wilson, David R Lynch.
       BACKGROUND: Friedreich's ataxia (FRDA), most commonly caused by a GAA triplet repeat (GAA-TR) expansion in intron 1 of the FXN gene, is characterized by deficiency of frataxin protein and clinical features such as progressive ataxia, dysarthria, impaired proprioception and vibration, abolished deep tendon reflexes, Babinski sign, and vision loss in association with non-neurological features such as skeletal anomalies, hearing loss, cardiomyopathy, and diabetes. Pathogenic GAA-TRs range in size from 60 to 1500 triplets and negatively correlate with age of onset. Clinical severity is predicted by a combination of GAA-TR length and disease duration (DD) via multivariable regressions, which cannot typically be used for the small sample sizes in most studies on this rare disease.
    OBJECTIVE: We aimed to develop a single metric, which we call "disease burden" (DB), that encompasses both GAA-TR length and DD for predicting disease features of FRDA in small sample sizes.
    METHODS: Linear regression and multivariable regression analysis was used to determine correlation coefficients between different disease features of FRDA.
    RESULTS: Using large datasets for validation, we found that DB predicts measures of neurological dysfunction in FRDA better than GAA-TR length or DD. Analogous results were found using small datasets.
    CONCLUSIONS: FRDA DB is a novel metric of disease severity that has utility in small datasets to demonstrate correlations that would not otherwise be evident with either GAA-TR or DD alone. This is important for discovering new biomarkers, as well as improving the prediction of severity of disease features in FRDA. © 2023 International Parkinson and Movement Disorder Society.
    Keywords:  ataxia; disease burden; multivariable regression; triplet repeat expansion
    DOI:  https://doi.org/10.1002/mds.29370
  23. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00123-5. [Epub ahead of print]83(6): 890-910
    Mitochondrial protein transport: Versatility of translocases and mechanisms.
    Jakob D Busch, Laura F Fielden, Nikolaus Pfanner, Nils Wiedemann.
      Biogenesis of mitochondria requires the import of approximately 1,000 different precursor proteins into and across the mitochondrial membranes. Mitochondria exhibit a wide variety of mechanisms and machineries for the translocation and sorting of precursor proteins. Five major import pathways that transport proteins to their functional intramitochondrial destination have been elucidated; these pathways range from the classical amino-terminal presequence-directed pathway to pathways using internal or even carboxy-terminal targeting signals in the precursors. Recent studies have provided important insights into the structural organization of membrane-embedded preprotein translocases of mitochondria. A comparison of the different translocases reveals the existence of at least three fundamentally different mechanisms: two-pore-translocase, β-barrel switching, and transport cavities open to the lipid bilayer. In addition, translocases are physically engaged in dynamic interactions with respiratory chain complexes, metabolite transporters, quality control factors, and machineries controlling membrane morphology. Thus, mitochondrial preprotein translocases are integrated into multi-functional networks of mitochondrial and cellular machineries.
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.020
  24. Cerebellum. 2023 Mar 15.
    Scale for the Assessment and Rating of Ataxia (SARA): Development of a Training Tool and Certification Program.
    Marcus Grobe-Einsler, Arian Taheri Amin, Jennifer Faber, Hartmut Völkel, Matthis Synofzik, Thomas Klockgether.
      Monitoring of disease severity is of great importance for treatment and management of clinical trials. The Scale for Assessment and Rating of Ataxia (SARA) is a frequently used, short and easily applicable clinical scale used to assess the severity of ataxia. The objective of our study was to develop a training and certification tool for the SARA. SARA scores were recorded according to a standardized protocol and rated by three clinical experts in consensus. Four hundred thirty-eight videos of 67 patients were included in the SARA training tool. The tutorial section demonstrates a complete SARA examination on a healthy control. In the training section, users can compare their ratings to consensus ratings and access a video library covering the complete SARA range. The tool also includes a section that allows optional certification. The SARA training tool provides comprehensive and standardized training material and certification to reduce variability in applying the SARA. Standardization aims to improve the quality of patient care and research in ataxia.
    Keywords:  Ataxia; Certification; SARA; Training tool
    DOI:  https://doi.org/10.1007/s12311-023-01543-3
  25. Cell Commun Signal. 2023 Mar 13. 21(1): 55
    FGF19 increases mitochondrial biogenesis and fusion in chondrocytes via the AMPKα-p38/MAPK pathway.
    Shiyi Kan, Caixia Pi, Li Zhang, Daimo Guo, Zhixing Niu, Yang Liu, Mengmeng Duan, Xiahua Pu, Mingru Bai, Chenchen Zhou, Demao Zhang, Jing Xie.
      Fibroblast growth factor 19 (FGF19) is recognized to play an essential role in cartilage development and physiology, and has emerged as a potential therapeutic target for skeletal metabolic diseases. However, FGF19-mediated cellular behavior in chondrocytes remains a big challenge. In the current study, we aimed to investigate the role of FGF19 on chondrocytes by characterizing mitochondrial biogenesis and fission-fusion dynamic equilibrium and exploring the underlying mechanism. We first found that FGF19 enhanced mitochondrial biogenesis in chondrocytes with the help of β Klotho (KLB), a vital accessory protein for assisting the binding of FGF19 to its receptor, and the enhanced biogenesis accompanied with a fusion of mitochondria, reflecting in the elongation of individual mitochondria and the up-regulation of mitochondrial fusion proteins. We then revealed that FGF19-mediated mitochondrial biogenesis and fusion required the binding of FGF19 to the membrane receptor, FGFR4, and the activation of AMP-activated protein kinase alpha (AMPKα)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α)/sirtuin 1 (SIRT1) axis. Finally, we demonstrated that FGF19-mediated mitochondrial biogenesis and fusion was mainly dependent on the activation of p-p38 signaling. Inhibition of p38 signaling largely reduced the high expression of AMPKα/PGC-1α/SIRT1 axis, decreased the up-regulation of mitochondrial fusion proteins and impaired the enhancement of mitochondrial network morphology in chondrocytes induced by FGF19. Taking together, our results indicate that FGF19 could increase mitochondrial biogenesis and fusion via AMPKα-p38/MAPK signaling, which enlarge the understanding of FGF19 on chondrocyte metabolism. Video Abstract.
    Keywords:  Chondrocyte; FGF19; Mitochondrial biogenesis; Mitochondrial fission–fusion; p38/MAPK signaling
    DOI:  https://doi.org/10.1186/s12964-023-01069-5
  26. Mitochondrion. 2023 Mar 10. pii: S1567-7249(23)00027-2. [Epub ahead of print]70 8-19
    A comprehensive perspective of Huntington's disease and mitochondrial dysfunction.
    Yinghong Dai, Haonan Wang, Aojie Lian, Jinchen Li, Guihu Zhao, Shenghui Hu, Bin Li.
      Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. It is caused by the expansion of the CAG trinucleotide repeat sequence in the HTT gene. HD mainly manifests as involuntary dance-like movements and severe mental disorders. As it progresses, patients lose the ability to speak, think, and even swallow. Although the pathogenesis is unclear, studies have found that mitochondrial dysfunctions occupy an important position in the pathogenesis of HD. Based on the latest research advances, this review sorts out and discusses the role of mitochondrial dysfunction on HD in terms of bioenergetics, abnormal autophagy, and abnormal mitochondrial membranes. This review provides researchers with a more complete perspective on the mechanisms underlying the relationship between mitochondrial dysregulation and HD.
    Keywords:  Bioenergetics; Huntington's disease; Mitochondrial Dynamics; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2023.03.001
  27. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00028-X. [Epub ahead of print]83(6): 1012-1012.e1
    SnapShot: Mitochondrial signaling.
    Taylor A Poor, Navdeep S Chandel.
      Mitochondria have emerged as signaling organelles with roles beyond their well-established function in generating ATP and metabolites for macromolecule synthesis. Healthy mitochondria integrate various physiologic inputs and communicate signals that control cell function or fate as well as adaptation to stress. Dysregulation of these mitochondrial signaling networks are linked to pathology. Here we outline a few modes of signaling between the mitochondrion and the cytoplasm. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.molcel.2023.01.008
  28. Brain. 2023 Mar 13. pii: awad080. [Epub ahead of print]
    The Italian reappraisal on the most frequent genetic defects in hereditary optic neuropathies and the global top 10.
    Claudio Fiorini, Danara Ormanbekova, Flavia Palombo, Michele Carbonelli, Giulia Amore, Martina Romagnoli, Pietro d'Agati, Maria Lucia Valentino, Piero Barboni, Maria Lucia Cascavilla, Annamaria De Negri, Federico Sadun, Arturo Carta, Francesco Testa, Vittoria Petruzzella, Silvana Guerriero, Stefania Bianchi Marzoli, Valerio Carelli, Chiara La Morgia, Leonardo Caporali.
      
    DOI:  https://doi.org/10.1093/brain/awad080
  29. Nature. 2023 Mar 15.
    Spatial mapping of mitochondrial networks and bioenergetics in lung cancer.
    Mingqi Han, Eric A Bushong, Mayuko Segawa, Alexandre Tiard, Alex Wong, Morgan R Brady, Milica Momcilovic, Dane M Wolf, Ralph Zhang, Anton Petcherski, Matthew Madany, Shili Xu, Jason T Lee, Masha V Poyurovsky, Kellen Olszewski, Travis Holloway, Adrian Gomez, Maie St John, Steven M Dubinett, Carla M Koehler, Orian S Shirihai, Linsey Stiles, Aaron Lisberg, Stefano Soatto, Saman Sadeghi, Mark H Ellisman, David B Shackelford.
      Mitochondria are critical to the governance of metabolism and bioenergetics in cancer cells1. The mitochondria form highly organized networks, in which their outer and inner membrane structures define their bioenergetic capacity2,3. However, in vivo studies delineating the relationship between the structural organization of mitochondrial networks and their bioenergetic activity have been limited. Here we present an in vivo structural and functional analysis of mitochondrial networks and bioenergetic phenotypes in non-small cell lung cancer (NSCLC) using an integrated platform consisting of positron emission tomography imaging, respirometry and three-dimensional scanning block-face electron microscopy. The diverse bioenergetic phenotypes and metabolic dependencies we identified in NSCLC tumours align with distinct structural organization of mitochondrial networks present. Further, we discovered that mitochondrial networks are organized into distinct compartments within tumour cells. In tumours with high rates of oxidative phosphorylation (OXPHOSHI) and fatty acid oxidation, we identified peri-droplet mitochondrial networks wherein mitochondria contact and surround lipid droplets. By contrast, we discovered that in tumours with low rates of OXPHOS (OXPHOSLO), high glucose flux regulated perinuclear localization of mitochondria, structural remodelling of cristae and mitochondrial respiratory capacity. Our findings suggest that in NSCLC, mitochondrial networks are compartmentalized into distinct subpopulations that govern the bioenergetic capacity of tumours.
    DOI:  https://doi.org/10.1038/s41586-023-05793-3
  30. J Cell Biochem. 2023 Mar 16.
    Role of VPS39, a key tethering protein for endolysosomal trafficking and mitochondria-lysosome crosstalk, in health and disease.
    Hanbing Li, Wenwen Gong, Weiyun Sun, Yuanfa Yao, Yubing Han.
      The coordinated interaction between mitochondria and lysosomes, mainly manifested by mitophagy, mitochondria-derived vesicles, and direct physical contact, is essential for maintaining cellular life activities. The VPS39 subunit of the homotypic fusion and protein sorting complex could play a key role in the regulation of organelle dynamics, such as endolysosomal trafficking and mitochondria-vacuole/lysosome crosstalk, thus contributing to a variety of physiological functions. The abnormalities of VPS39 and related subunits have been reported to be involved in the pathological process of some diseases. Here, we analyze the potential mechanisms and the existing problems of VPS39 in regulating organelle dynamics, which, in turn, regulate physiological functions and disease pathogenesis, so as to provide new clues for facilitating the discovery of therapeutic targets for mitochondrial and lysosomal diseases.
    Keywords:  HOPS complex; VPS39; diseases; endolysosomal trafficking; mitochondria-lysosome crosstalk
    DOI:  https://doi.org/10.1002/jcb.30396
  31. Mitochondrion. 2023 Mar 13. pii: S1567-7249(23)00029-6. [Epub ahead of print]
    Exploring the role of mitochondria transfer/transplant and their long-non-coding RNAs in regenerative therapies for skin aging.
    Sebastian Peñaherrera, Cristina Ruiz, Verónica Castañeda, Kathryn Livingston, Diego Barba, Verónica A Burzio, Andrés Caicedo, Keshav K Singh.
      Advancing age and environmental stressors lead to mitochondrial dysfunction in the skin, inducing premature aging, impaired regeneration, and greater risk of cancer. Cells rely on the communication between the mitochondria and the nucleus by tight regulation of long non-coding RNAs (lncRNAs) to avoid premature aging and maintain healthy skin. LncRNAs act as key regulators of cell proliferation, differentiation, survival, and maintenance of skin structure. However, research on how the lncRNAs are dysregulated during aging and due to stressors is needed to develop therapies to regenerate skin's function and structure. In this article, we discuss how age and environmental stressors may alter lncRNA homeodynamics, compromising cell survival and skin health, and how these factors may become inducers of skin aging. We describe skin cell types and how they depend on mitochondrial function and lncRNAs. We also provide a list of mitochondria localized and nuclear lncRNAs that can serve to better understand skin aging. Using bioinformatic prediction tools, we predict possible functions of lncRNAs based on their subcellular localization. We also search for experimentally determined protein interactions and the biological processes involved. Finally, we provide therapeutic strategies based on gene editing and mitochondria transfer/transplant (AMT/T) to restore lncRNA regulation and skin health. This article offers a unique perspective in understanding and defining the therapeutic potential of mitochondria localized lncRNAs (mt-lncRNAs) produced and AMT/T to treat skin aging and related diseases.
    Keywords:  AMT/T; Skin; aging; artificial mitochondrial transfer / transplant; gene editing; lncRNAs; mitochondria
    DOI:  https://doi.org/10.1016/j.mito.2023.02.012
  32. Protein Cell. 2022 Aug 23. pii: pwac037. [Epub ahead of print]
    4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis.
    Yifang He, Qianzhao Ji, Zeming Wu, Yusheng Cai, Jian Yin, Yiyuan Zhang, Sheng Zhang, Xiaoqian Liu, Weiqi Zhang, Guang-Hui Liu, Si Wang, Moshi Song, Jing Qu.
      Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These f indings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.
    Keywords:  4E-BP1; aging; mitochondria
    DOI:  https://doi.org/10.1093/procel/pwac037
  33. Cell Death Dis. 2023 Mar 16. 14(3): 199
    Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.
    Ananth Ponneri Babuharisankar, Cheng-Liang Kuo, Han-Yu Chou, Vidhya Tangeda, Chi-Chen Fan, Chung-Hsing Chen, Yung-Hsi Kao, Alan Yueh-Luen Lee.
      During hypoxia, FUNDC1 acts as a mitophagy receptor and accumulates at the ER (endoplasmic reticulum)-mitochondria contact sites (EMC), also called mitochondria-associated membranes (MAM). In mitophagy, the ULK1 complex phosphorylates FUNDC1(S17) at the EMC site. However, how mitochondria sense the stress and send the signal from the inside to the outside of mitochondria to trigger mitophagy is still unclear. Mitochondrial Lon was reported to be localized at the EMC under stress although the function remained unknown. In this study, we explored the mechanism of how mitochondrial sensors of hypoxia trigger and stabilize the FUNDC1-ULK1 complex by Lon in the EMC for cell survival and cancer progression. We demonstrated that Lon is accumulated in the EMC and associated with FUNDC1-ULK1 complex to induce mitophagy via chaperone activity under hypoxia. Intriguingly, we found that Lon-induced mitophagy is through binding with mitochondrial Na+/Ca2+ exchanger (NCLX) to promote FUNDC1-ULK1-mediated mitophagy at the EMC site in vitro and in vivo. Accordingly, our findings highlight a novel mechanism responsible for mitophagy initiation under hypoxia by chaperone Lon in mitochondria through the interaction with FUNDC1-ULK1 complex at the EMC site. These findings provide a direct correlation between Lon and mitophagy on cell survival and cancer progression.
    DOI:  https://doi.org/10.1038/s41419-023-05723-1
  34. EMBO J. 2023 Mar 13. e110597
    DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity.
    Xinyuan Wang, Huabin Zhang, Yuqin Wang, Laylan Bramasole, Kai Guo, Fatima Mourtada, Thomas Meul, Qianjiang Hu, Valeria Viteri, Ilona Kammerl, Melanie Konigshoff, Mareike Lehmann, Thomas Magg, Fabian Hauck, Isis E Fernandez, Silke Meiners.
      The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, antiviral adaptive immunity, autoimmunity, and is also part of a broader response to stress. Whether the immunoproteasome is regulated by DNA stress, however, is not known. We here demonstrate that mitochondrial DNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling resulting in cell autonomous activation of CD8+ T cells. The cGAS/STING-induced adaptive immune response is also observed in response to genomic DNA and is conserved in epithelial and mesenchymal cells of mice and men. In patients with idiopathic pulmonary fibrosis, chronic activation of the cGAS/STING-induced adaptive immune response in aberrant lung epithelial cells concurs with CD8+ T-cell activation in diseased lungs. Genetic depletion of the immunoproteasome and specific immunoproteasome inhibitors counteract DNA stress induced cytotoxic CD8+ T-cell activation. Our data thus unravel cytoplasmic DNA sensing via the cGAS/STING pathway as an activator of the immunoproteasome and CD8+ T cells. This represents a novel potential pathomechanism for pulmonary fibrosis that opens new therapeutic perspectives.
    Keywords:  CD8+ T cells; cGAS/STING; fibrosis; immunoproteasome; mitochondria
    DOI:  https://doi.org/10.15252/embj.2022110597
  35. Nature. 2023 Mar 15.
    Diversity of mitochondrial networks in lung cancer imaged.
      
    Keywords:  Cancer; Cell biology; Imaging
    DOI:  https://doi.org/10.1038/d41586-023-00427-0
  36. Front Cell Neurosci. 2023 ;17 1140916
    Mitophagy in ototoxicity.
    Hezhou Han, Sainan Hu, Yue Hu, Dongliang Liu, Junbo Zhou, Xiaofang Liu, Xiulan Ma, Yaodong Dong.
      Mitochondrial dysfunction is associated with ototoxicity, which is caused by external factors. Mitophagy plays a key role in maintaining mitochondrial homeostasis and function and is regulated by a series of key mitophagy regulatory proteins and signaling pathways. The results of ototoxicity models indicate the importance of this process in the etiology of ototoxicity. A number of recent investigations of the control of cell fate by mitophagy have enhanced our understanding of the mechanisms by which mitophagy regulates ototoxicity and other hearing-related diseases, providing opportunities for targeting mitochondria to treat ototoxicity.
    Keywords:  PINK1-Parkin; autophagy receptors; mitochondria; mitophagy; ototoxicity
    DOI:  https://doi.org/10.3389/fncel.2023.1140916
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