bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023‒11‒12
fifty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
  2. Mitophagy Activation by Urolithin A to Target Muscle Aging.
  3. ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.
  4. The mitochondrial respiratory chain.
  5. Epilepsy and Coenzyme Q10 deficiency with COQ4 variants.
  6. Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms.
  7. Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.
  8. Correction of a homoplasmic mitochondrial tRNA mutation in patient-derived iPSCs via a mitochondrial base editor.
  9. Regulation of mitochondrial structure by the actin cytoskeleton.
  10. A century of mitochondrial research, 1922-2022.
  11. A review for the correlation between optic atrophy 1-dependent mitochondrial fusion and cardiovascular disorders.
  12. S-adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review.
  13. Spatially resolved mapping of proteome turnover dynamics with subcellular precision.
  14. The Importance of Mitochondrial Disease Testing in Young Adults With New Onset Sensorineural Hearing Loss.
  15. Mitochondrial AAA+ proteases.
  16. Temporal dynamics of muscle mitochondrial uncoupling-induced integrated stress response and ferroptosis defense.
  17. Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice.
  18. Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.
  19. A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review.
  20. Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.
  21. Long-Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease.
  22. Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
  23. Mitochondrial 3-hydroxymethylglutaryl-CoA synthase-2 (HMGCS2) deficiency: a rare case with bicytopenia and coagulopathy.
  24. The Reactome Pathway Knowledgebase 2024.
  25. Mitohormesis.
  26. Mitochondrial DNA-triggered innate immune response: mechanisms and diseases.
  27. The power and potential of mitochondria transfer.
  28. Mitochondrial Permeability Transition Regulator, Cyclophilin D, is Transcriptionally Activated by C/EBP During Adipogenesis.
  29. Mitochondrial disorders as a mechanism for the development of obese Sarcopenia.
  30. Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for rare disease patients in a publicly-funded healthcare system: a prospective cohort study.
  31. A novel pathogenic variant in the SCA25-related gene expanding the etiology of early-onset and progressive cerebellar ataxia in childhood.
  32. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
  33. Mitochondrial regulation in human pluripotent stem cells during reprogramming and β cell differentiation.
  34. The inhibition of inner mitochondrial fusion in hepatocytes reduces NAFL and improves metabolic profile during obesity by modulating bile acid conjugation.
  35. Hepatic palmitoyl-proteomes and acyl-protein thioesterase protein proximity networks link lipid modification and mitochondria.
  36. Transfer of massive mitochondria from astrocytes reduce propofol neurotoxicity.
  37. Interaction between the mitochondrial adaptor MIRO and the motor adaptor TRAK.
  38. Protocol for isolating mice skeletal muscle myoblasts and myotubes via differential antibody validation.
  39. FUNDC1 collaborates with PINK1 in regulating mitochondrial Fission and compensating for PINK1 deficiency.
  40. International Undiagnosed Diseases Programs (UDPs): components and outcomes.
  41. Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview.
  42. Dual stop codon suppression in mammalian cells with genomically integrated genetic code expansion machinery.
  43. Sperm bud mitochondria to adjust the numbers.
  44. Patients with primary carnitine deficiency treated with L-carnitine are alive and doing well-A 10-year follow-up in the Faroe Islands.
  45. From workout to molecular switches: How does skeletal muscle produce, sense, and transduce subcellular redox signals?
  46. De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.
  47. Physical Contacts Between Mitochondria and WPBs Participate in WPB Maturation.
  48. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.
  49. Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.
  50. SIRT1 inhibits mitochondrial hyperfusion associated mito-bulb formation to sensitize oral cancer cells for apoptosis in a mtROS-dependent signalling pathway.
  1. EMBO J. 2023 Nov 07. e114054
    Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
    Kailash Venkatraman, Christopher T Lee, Guadalupe C Garcia, Arijit Mahapatra, Daniel Milshteyn, Guy Perkins, Keun-Young Kim, H Amalia Pasolli, Sebastien Phan, Jennifer Lippincott-Schwartz, Mark H Ellisman, Padmini Rangamani, Itay Budin.
      Cristae are high-curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous lipid-based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low-oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM.
    Keywords:  cardiolipin; cristae; lipids; mechanics; mitochondria
    DOI:  https://doi.org/10.15252/embj.2023114054
  2. Calcif Tissue Int. 2023 Nov 05.
    Mitophagy Activation by Urolithin A to Target Muscle Aging.
    Julie Faitg, Davide D'Amico, Chris Rinsch, Anurag Singh.
      The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserving the natural mitochondrial dynamic process, via fusion and fission, and by ensuring the removal of damaged mitochondria through mitophagy. During aging, mitophagy levels decline and negatively impact skeletal muscle performance. Nutritional and pharmacological approaches have been proposed to manage the decline in muscle function due to impaired mitochondria bioenergetics. The natural postbiotic Urolithin A has been shown to promote mitophagy, mitochondrial function and improved muscle function across species in different experimental models and across multiple clinical studies. In this review, we explore the biology of Urolithin A and the clinical evidence of its impact on promoting healthy skeletal muscles during age-associated muscle decline.
    Keywords:  Aging; Mitochondria; Mitophagy; Muscle health; Urolithin A
    DOI:  https://doi.org/10.1007/s00223-023-01145-5
  3. Life Sci Alliance. 2024 Jan;pii: e202302335. [Epub ahead of print]7(1):
    ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.
    Alexandre Janer, Jordan L Morris, Michiel Krols, Hana Antonicka, Mari J Aaltonen, Zhen-Yuan Lin, Hanish Anand, Anne-Claude Gingras, Julien Prudent, Eric A Shoubridge.
      Mitochondria interact with the ER at structurally and functionally specialized membrane contact sites known as mitochondria-ER contact sites (MERCs). Combining proximity labelling (BioID), co-immunoprecipitation, confocal microscopy and subcellular fractionation, we found that the ER resident SMP-domain protein ESYT1 was enriched at MERCs, where it forms a complex with the outer mitochondrial membrane protein SYNJ2BP. BioID analyses using ER-targeted, outer mitochondrial membrane-targeted, and MERC-targeted baits, confirmed the presence of this complex at MERCs and the specificity of the interaction. Deletion of ESYT1 or SYNJ2BP reduced the number and length of MERCs. Loss of the ESYT1-SYNJ2BP complex impaired ER to mitochondria calcium flux and provoked a significant alteration of the mitochondrial lipidome, most prominently a reduction of cardiolipins and phosphatidylethanolamines. Both phenotypes were rescued by reexpression of WT ESYT1 and an artificial mitochondria-ER tether. Together, these results reveal a novel function for ESYT1 in mitochondrial and cellular homeostasis through its role in the regulation of MERCs.
    DOI:  https://doi.org/10.26508/lsa.202302335
  4. Enzymes. 2023 ;pii: S1874-6047(23)00004-5. [Epub ahead of print]54 15-36
    The mitochondrial respiratory chain.
    Mårten Wikström, Cristina Pecorilla, Vivek Sharma.
      We present a brief review of the mitochondrial respiratory chain with emphasis on complexes I, III and IV, which contribute to the generation of protonmotive force across the inner mitochondrial membrane, and drive the synthesis of ATP by the process called oxidative phosphorylation. The basic structural and functional details of these complexes are discussed. In addition, we briefly review the information on the so-called supercomplexes, aggregates of complexes I-IV, and summarize basic physiological aspects of cell respiration.
    Keywords:  Bioenergetics; Cell respiration; Cytochromes; Electron transfer; Oxidative phosphorylation; Oxygen consumption; Proton pumping; Proton transfer; Protonmotive force; Supercomplexes
    DOI:  https://doi.org/10.1016/bs.enz.2023.05.001
  5. Epilepsy Behav. 2023 Nov 08. pii: S1525-5050(23)00417-1. [Epub ahead of print]149 109498
    Epilepsy and Coenzyme Q10 deficiency with COQ4 variants.
    Chia-Jui Hsu, Wang-Tso Lee.
      Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.
    Keywords:  COQ4; Children; Coenzyme Q10 deficiency; Epilepsy; Mitochondria
    DOI:  https://doi.org/10.1016/j.yebeh.2023.109498
  6. Nat Commun. 2023 Nov 08. 14(1): 7207
    Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms.
    Louis Tung Faat Lai, Jayashree Balaraman, Fei Zhou, Doreen Matthies.
      Magnesium ions (Mg2+) play an essential role in cellular physiology. In mitochondria, protein and ATP synthesis and various metabolic pathways are directly regulated by Mg2+. MRS2, a magnesium channel located in the inner mitochondrial membrane, mediates the influx of Mg2+ into the mitochondrial matrix and regulates Mg2+ homeostasis. Knockdown of MRS2 in human cells leads to reduced uptake of Mg2+ into mitochondria and disruption of the mitochondrial metabolism. Despite the importance of MRS2, the Mg2+ translocation and regulation mechanisms of MRS2 are still unclear. Here, using cryo-EM we report the structures of human MRS2 in the presence and absence of Mg2+ at 2.8 Å and 3.3 Å, respectively. From the homo-pentameric structures, we identify R332 and M336 as major gating residues, which are then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds is found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg2+-binding sites are identified in the MRS2 soluble domain, distinct from the two sites previously reported in CorA, a homolog of MRS2 in prokaryotes. Altogether, this study provides the molecular basis for understanding the Mg2+ translocation and regulatory mechanisms of MRS2.
    DOI:  https://doi.org/10.1038/s41467-023-42599-3
  7. Cytotherapy. 2023 Nov 06. pii: S1465-3249(23)01076-9. [Epub ahead of print]
    Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.
    Yanyan Gao, Linlin Guo, Fei Wang, Yin Wang, Peifeng Li, Dejiu Zhang.
      Mitochondrial DNA (mtDNA) is a critical genome contained within the mitochondria of eukaryotic cells, with many copies present in each mitochondrion. Mutations in mtDNA often are inherited and can lead to severe health problems, including various inherited diseases and premature aging. The lack of efficient repair mechanisms and the susceptibility of mtDNA to damage exacerbate the threat to human health. Heteroplasmy, the presence of different mtDNA genotypes within a single cell, increases the complexity of these diseases and requires an effective editing method for correction. Recently, gene-editing techniques, including programmable nucleases such as restriction endonuclease, zinc finger nuclease, transcription activator-like effector nuclease, clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated 9 and base editors, have provided new tools for editing mtDNA in mammalian cells. Base editors are particularly promising because of their high efficiency and precision in correcting mtDNA mutations. In this review, we discuss the application of these techniques in mitochondrial gene editing and their limitations. We also explore the potential of base editors for mtDNA modification and discuss the opportunities and challenges associated with their application in mitochondrial gene editing. In conclusion, this review highlights the advancements, limitations and opportunities in current mitochondrial gene-editing technologies and approaches. Our insights aim to stimulate the development of new editing strategies that can ultimately alleviate the adverse effects of mitochondrial hereditary diseases.
    Keywords:  DddA-derived cytosine base editors (DdCBEs); adenoviruses; mitochondrial DNA (mtDNA); mitochondrially targeted nucleases; mtDNA editing technology; mtDNA heteroplasmy
    DOI:  https://doi.org/10.1016/j.jcyt.2023.10.004
  8. Commun Biol. 2023 Nov 03. 6(1): 1116
    Correction of a homoplasmic mitochondrial tRNA mutation in patient-derived iPSCs via a mitochondrial base editor.
    Xiaoxu Chen, Mingyue Chen, Yuqing Zhu, Haifeng Sun, Yue Wang, Yuan Xie, Lianfu Ji, Cheng Wang, Zhibin Hu, Xuejiang Guo, Zhengfeng Xu, Jun Zhang, Shiwei Yang, Dong Liang, Bin Shen.
      Pathogenic mutations in mitochondrial DNA cause severe and often lethal multi-system symptoms in primary mitochondrial defects. However, effective therapies for these defects are still lacking. Strategies such as employing mitochondrially targeted restriction enzymes or programmable nucleases to shift the ratio of heteroplasmic mutations and allotopic expression of mitochondrial protein-coding genes have limitations in treating mitochondrial homoplasmic mutations, especially in non-coding genes. Here, we conduct a proof of concept study applying a screened DdCBE pair to correct the homoplasmic m.A4300G mutation in induced pluripotent stem cells derived from a patient with hypertrophic cardiomyopathy. We achieve efficient G4300A correction with limited off-target editing, and successfully restore mitochondrial function in corrected induced pluripotent stem cell clones. Our study demonstrates the feasibility of using DdCBE to treat primary mitochondrial defects caused by homoplasmic pathogenic mitochondrial DNA mutations.
    DOI:  https://doi.org/10.1038/s42003-023-05500-y
  9. Cytoskeleton (Hoboken). 2023 Nov 06.
    Regulation of mitochondrial structure by the actin cytoskeleton.
    Yihe Wu, Xiaoyu Ren, Peng Shi, Congying Wu.
      Mitochondria are the powerhouse of the cell and play important roles in multiple cellular processes including cell metabolism, proliferation, and programmed cell death. Mitochondria are double-membrane organelles with the inner membrane folding inward to form cristae. Mitochondria networks undergo dynamic fission and fusion. Deregulation of mitochondrial structure has been linked to perturbed mitochondrial membrane potential and disrupted metabolism, as evidenced in tumorigenesis, neurodegenerative diseases, etc. Actin and its motors-myosins have long been known to generate mechanical forces and participate in short-distance cargo transport. Accumulating knowledge from biochemistry and live cell/electron microscope imaging has demonstrated the role of actin filaments in pre-constricting the mitochondria during fission. Recent studies have suggested the involvement of myosins in cristae maintenance and mitochondria quality control. Here, we review current findings and discuss future directions in the emerging fields of cytoskeletal regulation in cristae formation, mitochondrial dynamics, intracellular transport, and mitocytosis, with focus on the actin cytoskeleton and its motor proteins.
    Keywords:  actin; cristae structure; mechanical force; mitochondria; myosin
    DOI:  https://doi.org/10.1002/cm.21804
  10. Enzymes. 2023 ;pii: S1874-6047(23)00008-2. [Epub ahead of print]54 37-70
    A century of mitochondrial research, 1922-2022.
    Howard T Jacobs.
      Although recognized earlier as subcellular entities by microscopists, mitochondria have been the subject of functional studies since 1922, when their biochemical similarities with bacteria were first noted. In this overview I trace the history of research on mitochondria from that time up to the present day, focussing on the major milestones of the overlapping eras of mitochondrial biochemistry, genetics, pathology and cell biology, and its explosion into new areas in the past 25 years. Nowadays, mitochondria are considered to be fully integrated into cell physiology, rather than serving specific functions in isolation.
    Keywords:  Apoptosis; Calcium homeostasis; Cell signalling; Chemiosmotic hypothesis; DNA replication; Endosymbiosis; Eukaryote origins; Heteroplasmy; Immunity; Krebs cycle; Mitochondrial DNA; Mitochondrial disease; Mitochondrial dynamics; Mitophagy; Oxidative phosphorylation; Reactive oxygen species; Supercomplexes
    DOI:  https://doi.org/10.1016/bs.enz.2023.07.002
  11. Int J Biol Macromol. 2023 Nov 06. pii: S0141-8130(23)04809-2. [Epub ahead of print]254(Pt 2): 127910
    A review for the correlation between optic atrophy 1-dependent mitochondrial fusion and cardiovascular disorders.
    Bi-Feng Yao, Xiu-Ju Luo, Jun Peng.
      Mitochondrial dynamics homeostasis is sustained by continuous and balanced fission and fusion, which are determinants of morphology, abundance, biogenesis and mitophagy of mitochondria. Optic atrophy 1 (OPA1), as the only inner mitochondrial membrane fusion protein, plays a key role in stabilizing mitochondrial dynamics. The disturbance of mitochondrial dynamics contributes to the pathophysiological progress of cardiovascular disorders, which are the main cause of death worldwide in recent decades and result in tremendous social burden. In this review, we describe the latest findings regarding OPA1 and its role in mitochondrial fusion. We summarize the post-translational modifications (PTMs) for OPA1 and its regulatory role in mitochondrial dynamics. Then the diverse cell fates caused by OPA1 expression during cardiovascular disorders are discussed. Moreover, cardiovascular disorders (such as heart failure, myocardial ischemia/reperfusion injury, cardiomyopathy and cardiac hypertrophy) relevant to OPA1-dependent mitochondrial dynamics imbalance have been detailed. Finally, we highlight the potential that targeting OPA1 to impact mitochondrial fusion may be used as a novel strategy against cardiovascular disorders.
    Keywords:  Cardiovascular disorders; Cell death; Mitochondrial dynamics; Optic atrophy 1; Post-translation modification
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127910
  12. JIMD Rep. 2023 Nov;64(6): 417-423
    S-adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review.
    Angela Lee, Renatta Knox, Margaret Reynolds, Erin McRoy, Hoanh Nguyen.
      Phospho-ribosyl-pyrophosphate synthetase 1 (PRPS1) deficiency is secondary to loss of function variants in PRPS1. This enzyme generates phospho-ribosyl-pyrophosphate (PRPP), which is utilized in the synthesis of purines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP), among other metabolic pathways. Arts syndrome, or severe PRPS1 deficiency, is an X-linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age. Supplementation of the purine and NAD pathways outside of PRPP-dependent reactions is a logical approach and has been reported in a handful of patients, two with S-adenosylmethionine (SAMe) and one with SAMe and nicotinamide riboside (NR). We present the clinical course of a fourth Arts syndrome patient who was started on therapy and review previously reported patients. All patients had stability or improvement of symptoms, suggesting that SAMe and NR can be a treatment option in Arts syndrome, though further studies are warranted.
    Keywords:  Arts syndrome; PRPP; PRPS1; S‐adenosylmethionine; nicotinamide riboside; phosphoribosylpyrophosphate
    DOI:  https://doi.org/10.1002/jmd2.12395
  13. Nat Commun. 2023 Nov 08. 14(1): 7217
    Spatially resolved mapping of proteome turnover dynamics with subcellular precision.
    Feng Yuan, Yi Li, Xinyue Zhou, Peiyuan Meng, Peng Zou.
      Cellular activities are commonly associated with dynamic proteomic changes at the subcellular level. Although several techniques are available to quantify whole-cell protein turnover dynamics, such measurements often lack sufficient spatial resolution at the subcellular level. Herein, we report the development of prox-SILAC method that combines proximity-dependent protein labeling (APEX2/HRP) with metabolic incorporation of stable isotopes (pulse-SILAC) to map newly synthesized proteins with subcellular spatial resolution. We apply prox-SILAC to investigate proteome dynamics in the mitochondrial matrix and the endoplasmic reticulum (ER) lumen. Our analysis reveals a highly heterogeneous distribution in protein turnover dynamics within macromolecular machineries such as the mitochondrial ribosome and respiratory complexes I-V, thus shedding light on their mechanism of hierarchical assembly. Furthermore, we investigate the dynamic changes of ER proteome when cells are challenged with stress or undergoing stimulated differentiation, identifying subsets of proteins with unique patterns of turnover dynamics, which may play key regulatory roles in alleviating stress or promoting differentiation. We envision that prox-SILAC could be broadly applied to profile protein turnover at various subcellular compartments, under both physiological and pathological conditions.
    DOI:  https://doi.org/10.1038/s41467-023-42861-8
  14. Ear Hear. 2023 Nov 06.
    The Importance of Mitochondrial Disease Testing in Young Adults With New Onset Sensorineural Hearing Loss.
    Alaa Koleilat, Gayla L Poling, Lisa A Schimmenti, Linda Hasadsri.
      OBJECTIVES: Sensorineural hearing loss (SNHL) occurs commonly as part of mitochondriopathies and varies in severity and onset. In this study, we characterized hearing with specific consideration for hearing loss as a potential early indicator of mitochondrial disease (MD). We hypothesize that genetic testing at the earliest detection of SNHL may lead to an earlier MD diagnosis.DESIGN: We reviewed the clinical and audiometric data of 49 patients undergoing genetic testing for MD.
    RESULTS: One-third of individuals with molecularly confirmed MD presented with SNHL. On average, patients had hearing loss at least 10 years before genetic testing. The collective audiometric profile includes mild to moderate SNHL at lower frequencies and moderate SNHL at 2 kHz and higher frequencies.
    CONCLUSIONS: This study suggests that screening for SNHL could be an early indicator of MD. We propose that the audiometric profile for those with a MD diagnosis may have clinical triage utility.
    DOI:  https://doi.org/10.1097/AUD.0000000000001442
  15. Enzymes. 2023 ;pii: S1874-6047(23)00028-8. [Epub ahead of print]54 205-220
    Mitochondrial AAA+ proteases.
    Yuichi Matsushima.
      Mitochondria are multifunctional organelles that play a central role in a wide range of life-sustaining tasks in eukaryotic cells, including adenosine triphosphate (ATP) production, calcium storage and coenzyme generation pathways such as iron-sulfur cluster biosynthesis. The wide range of mitochondrial functions is carried out by a diverse array of proteins comprising approximately 1500 proteins or polypeptides. Degradation of these proteins is mainly performed by four AAA+ proteases localized in mitochondria. These AAA+ proteases play a quality control role in degrading damaged or misfolded proteins and perform various other functions. This chapter describes previously identified roles for these AAA+ proteases that are localized in the mitochondria of animal cells.
    Keywords:  AAA+ protease; ClpXP; Lon; Mitochondria; i-AAA; m-AAA
    DOI:  https://doi.org/10.1016/bs.enz.2023.09.002
  16. Front Endocrinol (Lausanne). 2023 ;14 1277866
    Temporal dynamics of muscle mitochondrial uncoupling-induced integrated stress response and ferroptosis defense.
    Carla Igual Gil, Alina Löser, Kristina Lossow, Maria Schwarz, Daniela Weber, Tilman Grune, Anna P Kipp, Susanne Klaus, Mario Ost.
      Mitochondria play multifaceted roles in cellular function, and impairments across domains of mitochondrial biology are known to promote cellular integrated stress response (ISR) pathways as well as systemic metabolic adaptations. However, the temporal dynamics of specific mitochondrial ISR related to physiological variations in tissue-specific energy demands remains unknown. Here, we conducted a comprehensive 24-hour muscle and plasma profiling of male and female mice with ectopic mitochondrial respiratory uncoupling in skeletal muscle (mUcp1-transgenic, TG). TG mice are characterized by increased muscle ISR, elevated oxidative stress defense, and increased secretion of FGF21 and GDF15 as ISR-induced myokines. We observed a temporal signature of both cell-autonomous and systemic ISR in the context of endocrine myokine signaling and cellular redox balance, but not of ferroptotic signature which was also increased in TG muscle. We show a progressive increase of muscle ISR on transcriptional level during the active phase (night time), with a subsequent peak in circulating FGF21 and GDF15 in the early resting phase. Moreover, we found highest levels of muscle oxidative defense (GPX and NQO1 activity) between the late active to early resting phase, which could aim to counteract excessive iron-dependent lipid peroxidation and ferroptosis in muscle of TG mice. These findings highlight the temporal dynamics of cell-autonomous and endocrine ISR signaling under skeletal muscle mitochondrial uncoupling, emphasizing the importance of considering such dissociation in translational strategies and sample collection for diagnostic biomarker analysis.
    Keywords:  FGF21; GDF15; circadian rhythm; ferroptosis; integrated stress response; mitochondrial uncoupling; oxidative stress; skeletal muscle
    DOI:  https://doi.org/10.3389/fendo.2023.1277866
  17. iScience. 2023 Nov 17. 26(11): 108196
    Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice.
    Nicole K H Yiew, Stanislaw Deja, Daniel Ferguson, Kevin Cho, Chaowapong Jarasvaraparn, Miriam Jacome-Sosa, Andrew J Lutkewitte, Sandip Mukherjee, Xiaorong Fu, Jason M Singer, Gary J Patti, Shawn C Burgess, Brian N Finck.
      The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by hepatocyte MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway and an indirect mitochondrial pathway requiring the MPC. Hepatocyte MPC deletion reduced the incorporation of 13C-glycerol into TCA cycle metabolites, but not into new glucose. Furthermore, suppression of glycerol and alanine metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice, suggesting multiple layers of redundancy in glycemic control in mice.
    Keywords:  Cellular physiology; Human metabolism
    DOI:  https://doi.org/10.1016/j.isci.2023.108196
  18. Cell Chem Biol. 2023 Oct 26. pii: S2451-9456(23)00367-7. [Epub ahead of print]
    Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.
    Valerie Perea, Kelsey R Baron, Vivian Dolina, Giovanni Aviles, Grace Kim, Jessica D Rosarda, Xiaoyan Guo, Martin Kampmann, R Luke Wiseman.
      The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly selective ISR activators.
    Keywords:  ISR; UPR; integrated stress response; pharmacologic activator; stress-responsive signaling pathway; unfolded protein response
    DOI:  https://doi.org/10.1016/j.chembiol.2023.10.006
  19. CNS Neurosci Ther. 2023 Nov 06.
    A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review.
    Xianjun Xuan, Jie Ruan, Chunhong Wu, Yiyi Gao, Lingfei Li, Xiaoguang Lei.
      BACKGROUND: Mitochondrial complex III (CIII) deficiency is an autosomal recessive disease characterized by symptoms such as ataxia, cognitive dysfunction, and spastic paraplegia. Multiple genes are associated with complex III defects. Among them, the mutation of TTC19 is a rare subtype.METHODS: We screened a Chinese boy with weakness of limbs and his non-consanguineous parents by whole exome sequencing and targeted sequencing.
    RESULTS: We report a Chinese boy diagnosed with mitochondrial complex III defect type 2 carrying a homozygous variant (c.719-732del, p.Leu240Serfs*17) of the TTC19 gene. According to the genotype analysis of his family members, this is an autosomal recessive inheritance. We provide his clinical manifestation.
    CONCLUSIONS: A new type of TTC19 mutation (c.719-732del, p.Leu240Serfs*17) was found, which enriched the TTC19 gene mutation spectrum and provided new data for elucidating the pathogenesis of CIII-deficient diseases.
    DOI:  https://doi.org/10.1111/cns.14425
  20. Basic Res Cardiol. 2023 Nov 06. 118(1): 47
    Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.
    Ilona Kutschka, Edoardo Bertero, Christina Wasmus, Ke Xiao, Lifeng Yang, Xinyu Chen, Yasuhiro Oshima, Marcus Fischer, Manuela Erk, Berkan Arslan, Lin Alhasan, Daria Grosser, Katharina J Ermer, Alexander Nickel, Michael Kohlhaas, Hanna Eberl, Sabine Rebs, Katrin Streckfuss-Bömeke, Werner Schmitz, Peter Rehling, Thomas Thum, Takahiro Higuchi, Joshua Rabinowitz, Christoph Maack, Jan Dudek.
      Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.
    Keywords:  Amino acid; Barth syndrome; Fatty acid oxidation; Metabolism; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1007/s00395-023-01017-x
  21. Mov Disord. 2023 Nov 05.
    Long-Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease.
    Kensuke Daida, Manabu Funayama, Kimberley J Billingsley, Laksh Malik, Abigail Miano-Burkhardt, Hampton L Leonard, Mary B Makarious, Hirotaka Iwaki, Jinhui Ding, J Raphael Gibbs, Mayu Ishiguro, Hiroyo Yoshino, Kotaro Ogaki, Genko Oyama, Kenya Nishioka, Risa Nonaka, Wado Akamatsu, Cornelis Blauwendraat, Nobutaka Hattori.
      BACKGROUND: Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants.OBJECTIVES: To identify complex structural variants in PRKN using long-read sequencing.
    METHODS: We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP-PD) and United Kingdom (UK)-Biobank datasets.
    RESULTS: Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression.
    CONCLUSIONS: This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read sequencing for structural variant analysis in unresolved young-onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
    Keywords:  PARK2; Parkinson's disease; inversion; long-read sequencing; structural variant
    DOI:  https://doi.org/10.1002/mds.29610
  22. Nat Aging. 2023 Nov 09.
    Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
    Chrysa Nikopoulou, Niklas Kleinenkuhnen, Swati Parekh, Tonantzi Sandoval, Christoph Ziegenhain, Farina Schneider, Patrick Giavalisco, Kat-Folz Donahue, Anna Juliane Vesting, Marcel Kirchner, Mihaela Bozukova, Christian Vossen, Janine Altmüller, Thomas Wunderlich, Rickard Sandberg, Vangelis Kondylis, Achim Tresch, Peter Tessarz.
      Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.
    DOI:  https://doi.org/10.1038/s43587-023-00513-y
  23. BMJ Case Rep. 2023 Nov 06. pii: e257011. [Epub ahead of print]16(11):
    Mitochondrial 3-hydroxymethylglutaryl-CoA synthase-2 (HMGCS2) deficiency: a rare case with bicytopenia and coagulopathy.
    Dalia El-Sayed, Hanaa El-Karaksy, Yasser Wali, Ilham Youssry.
      Mitochondrial 3-hydroxymethylglutaryl-CoA synthase-2 (HMGCS2) is the main enzyme involved in ketogenesis. It is an essential enzyme for the catalysis of β-oxidation-derived-acetyl-CoA and acetoacetyl Co-A to produce β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) and free coenzyme A.The deficiency of this enzyme (3-hydoxy-3-methylglutaryl-CoA synthase) is a very rare metabolic disorder with limited cases described in the literature. The manifestations of this disease include hypoketotic hypoglycaemia, metabolic acidosis, lethargy, hepatomegaly with fatty liver and encephalopathy.We report a middle childhood male who presented with hepatosplenomegaly, lymphadenopathy and bicytopenia. The case was diagnosed by the whole exome sequencing which revealed a homozygous missense variant of uncertain significance in HMGCS2 gene.
    Keywords:  Haematology (incl blood transfusion); Metabolic disorders
    DOI:  https://doi.org/10.1136/bcr-2023-257011
  24. Nucleic Acids Res. 2023 Nov 06. pii: gkad1025. [Epub ahead of print]
    The Reactome Pathway Knowledgebase 2024.
    Marija Milacic, Deidre Beavers, Patrick Conley, Chuqiao Gong, Marc Gillespie, Johannes Griss, Robin Haw, Bijay Jassal, Lisa Matthews, Bruce May, Robert Petryszak, Eliot Ragueneau, Karen Rothfels, Cristoffer Sevilla, Veronica Shamovsky, Ralf Stephan, Krishna Tiwari, Thawfeek Varusai, Joel Weiser, Adam Wright, Guanming Wu, Lincoln Stein, Henning Hermjakob, Peter D'Eustachio.
      The Reactome Knowledgebase (https://reactome.org), an Elixir and GCBR core biological data resource, provides manually curated molecular details of a broad range of normal and disease-related biological processes. Processes are annotated as an ordered network of molecular transformations in a single consistent data model. Reactome thus functions both as a digital archive of manually curated human biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. Here we review progress towards annotation of the entire human proteome, targeted annotation of disease-causing genetic variants of proteins and of small-molecule drugs in a pathway context, and towards supporting explicit annotation of cell- and tissue-specific pathways. Finally, we briefly discuss issues involved in making Reactome more fully interoperable with other related resources such as the Gene Ontology and maintaining the resulting community resource network.
    DOI:  https://doi.org/10.1093/nar/gkad1025
  25. Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00380-7. [Epub ahead of print]35(11): 1872-1886
    Mitohormesis.
    Yu-Wei Cheng, Jie Liu, Toren Finkel.
      Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.011
  26. Cell Mol Immunol. 2023 Nov 07.
    Mitochondrial DNA-triggered innate immune response: mechanisms and diseases.
    Ming-Ming Hu, Hong-Bing Shu.
      Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by the cGAS-MITA/STING pathway, resulting in the induced expression of type I interferon and other effector genes. These processes contribute to the innate immune response to viral infection and other stress factors. The deregulation of these processes causes autoimmune diseases, inflammatory metabolic disorders and cancer. Therefore, the cGAS-MITA/STING pathway is a potential target for intervention in infectious, inflammatory and autoimmune diseases as well as cancer. In this review, we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway, the effects of the pathway under various physiological and pathological conditions, and advances in the development of drugs that target cGAS and MITA/STING.
    Keywords:  Disease; Innate immunity; MITA/STING; Mitostress; Virus
    DOI:  https://doi.org/10.1038/s41423-023-01086-x
  27. Nature. 2023 Nov;623(7986): 283-291
    The power and potential of mitochondria transfer.
    Nicholas Borcherding, Jonathan R Brestoff.
      Mitochondria are believed to have originated through an ancient endosymbiotic process in which proteobacteria were captured and co-opted for energy production and cellular metabolism. Mitochondria segregate during cell division and differentiation, with vertical inheritance of mitochondria and the mitochondrial DNA genome from parent to daughter cells. However, an emerging body of literature indicates that some cell types export their mitochondria for delivery to developmentally unrelated cell types, a process called intercellular mitochondria transfer. In this Review, we describe the mechanisms by which mitochondria are transferred between cells and discuss how intercellular mitochondria transfer regulates the physiology and function of various organ systems in health and disease. In particular, we discuss the role of mitochondria transfer in regulating cellular metabolism, cancer, the immune system, maintenance of tissue homeostasis, mitochondrial quality control, wound healing and adipose tissue function. We also highlight the potential of targeting intercellular mitochondria transfer as a therapeutic strategy to treat human diseases and augment cellular therapies.
    DOI:  https://doi.org/10.1038/s41586-023-06537-z
  28. J Biol Chem. 2023 Nov 08. pii: S0021-9258(23)02486-9. [Epub ahead of print] 105458
    Mitochondrial Permeability Transition Regulator, Cyclophilin D, is Transcriptionally Activated by C/EBP During Adipogenesis.
    Chen Yu, Rubens Sautchuk, John Martinez, Roman A Eliseev.
      Age-related bone loss is associated with decreased bone formation, increased bone resorption and accumulation of bone marrow fat. During aging, differentiation potential of bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) is shifted towards an adipogenic lineage and away from an osteogenic lineage. In aged bone tissue, we previously observed pathological opening of the mitochondrial permeability transition pore (MPTP) which leads to mitochondrial dysfunction, oxidative phosphorylation uncoupling, and cell death. Cyclophilin D (CypD) is a mitochondrial protein that facilitates opening of the MPTP. We found earlier that CypD is downregulated during osteogenesis of BMSCs leading to lower MPTP activity and, thus, protecting mitochondria from dysfunction. However, during adipogenesis, a fate alternative to osteogenesis, the regulation of mitochondrial function and CypD expression is still unclear. In this study, we observed that BMSCs have increased CypD expression and MPTP activity, activated glycolysis, and fragmented mitochondrial network during adipogenesis. Adipogenic C/EBPα acts as a transcriptional activator of expression of the CypD gene, Ppif, during this process. Inflammation-associated transcription factor NF-κB shows a synergistic effect with C/EBPα inducing Ppif expression. Overall, we demonstrated changes in mitochondrial morphology and function during adipogenesis. We also identified C/EBPα as a transcriptional activator of CypD. The synergistic activation of CypD by C/EBPα and the NF-κB p65 subunit during this process suggests a potential link between adipogenic signaling, inflammation, and MPTP gain-of-function, thus altering BMSC fate during aging.
    Keywords:  Adipogenesis; C/EBP; Cyclophilin D; Mitochondrial permeability transition
    DOI:  https://doi.org/10.1016/j.jbc.2023.105458
  29. Diabetol Metab Syndr. 2023 Nov 06. 15(1): 224
    Mitochondrial disorders as a mechanism for the development of obese Sarcopenia.
    Tingfeng Liao, Lijiao Xiong, Xiaohao Wang, Shu Yang, Zhen Liang.
      Obese sarcopenia is a severe and prevalent disease in an aging society. Compared to sarcopenia alone, the development and advanced stage of obesity sarcopenia is faster and more severe. Diagnosis of the cause of adipocyte accumulation is also more complicated; however, no effective pharmacological treatment is available. Chronic inflammation is one of the causes of sarcopenia, and obese patients, who are more likely to develop chronic inflammation, may simultaneously suffer from obesity and sarcopenia. Mitochondrial metabolic disorders have been more easily observed in the tissue cells of patients with obesity and sarcopenia. Mitochondrial metabolic disorders include abnormal mtDNA release, mitochondrial autophagy, and dynamic mitochondrial disorders. Therefore, this review will reveal the mechanism of development of obesity myasthenia gravis from the perspective of mitochondria and discuss the currently existing small-molecule drugs.
    DOI:  https://doi.org/10.1186/s13098-023-01192-w
  30. Genet Med. 2023 Nov 01. pii: S1098-3600(23)01028-6. [Epub ahead of print] 101012
    Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for rare disease patients in a publicly-funded healthcare system: a prospective cohort study.
    Care4Rare Canada Consortium
      PURPOSE: To evaluate the diagnostic utility of publicly-funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases (RGDs).METHODS: We prospectively enrolled 297 probands who met eligibility criteria and received ES across five sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests.
    RESULTS: Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30-40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses.
    CONCLUSION: We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test.
    Keywords:  clinical validity; clinical-molecular diagnoses; exome sequencing; healthcare system; implementation science; rare disease
    DOI:  https://doi.org/10.1016/j.gim.2023.101012
  31. Neuropediatrics. 2023 Nov 07.
    A novel pathogenic variant in the SCA25-related gene expanding the etiology of early-onset and progressive cerebellar ataxia in childhood.
    Giulia Ferrera, Rossella Izzo, Daniele Ghezzi, Lorenzo Nanetti, Eleonora Lamantea, Anna Ardissone.
      Spinocerebellar ataxias (SCAs) are heterogeneous autosomal dominant progressive ataxic disorders. SCA25 has been linked to PNPT1 pathogenic variants. Although pediatric onset is not unusual, to date only one patient with onset in the first years of life has been reported. This study presents an additional case, wherein symptoms emerged during the toddler phase, accompanied by the identification of a novel PNPT1 variant. The childwas seen at 3 years because of frequent falls. Neurological examination revealed cerebellar signsand psychomotor delay. Brain MRI showed cerebellar atrophy (CA), cerebellar cortex and dentate nuclei hyperintensities. Metabolic and genetic testing was inconclusive. At follow up (age 6), the child had clinically and radiologically worsened; ENG revealed axonal sensory neuropathy. Screening of genes associated with ataxias and mitochondrial disease identified a novel, heterozygous variant in PNPT1, which was probably pathogenic. This variant was also detected in the proband's mother and maternal grandmother both asymptomatic, which aligns with the previously documented incomplete penetrance of heterozygous PNPT1 variants. Our study confirms that SCA25 can have onset in early-childhood and characterizes natural history in pediatric cases: progressive cerebellar ataxia, sensory neuropathy which manifests during the course of the disease. We report for the first time cerebellar gray matter hyperintensities, suggesting that SCA25 should be included in the differential diagnosis of cerebellar ataxias associated with such brain imaging features. In summary, SCA25 should be considered in the diagnostic workup of early onset pediatric progressive ataxias Additionally, we confirm an incomplete penetrance and highly variable expressivity of PNPT1-associated SCA25.
    DOI:  https://doi.org/10.1055/a-2205-2402
  32. Immunity. 2023 Oct 31. pii: S1074-7613(23)00444-2. [Epub ahead of print]
    Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
    Rui Miao, Cong Jiang, Winston Y Chang, Haiwei Zhang, Jinsu An, Felicia Ho, Pengcheng Chen, Han Zhang, Caroline Junqueira, Dulguun Amgalan, Felix G Liang, Junbing Zhang, Charles L Evavold, Iva Hafner-Bratkovič, Zhibin Zhang, Pietro Fontana, Shiyu Xia, Markus Waldeck-Weiermair, Youdong Pan, Thomas Michel, Liron Bar-Peled, Hao Wu, Jonathan C Kagan, Richard N Kitsis, Peng Zhang, Xing Liu, Judy Lieberman.
      Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.
    Keywords:  CRLS1; GSDMD; IL-1; PLSCR3; cardiolipin; mitochondria; pyroptosis
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.004
  33. Front Endocrinol (Lausanne). 2023 ;14 1236472
    Mitochondrial regulation in human pluripotent stem cells during reprogramming and β cell differentiation.
    Ila Tewari Jasra, Nerea Cuesta-Gomez, Kevin Verhoeff, Braulio A Marfil-Garza, Nidheesh Dadheech, A M James Shapiro.
      Mitochondria are the powerhouse of the cell and dynamically control fundamental biological processes including cell reprogramming, pluripotency, and lineage specification. Although remarkable progress in induced pluripotent stem cell (iPSC)-derived cell therapies has been made, very little is known about the role of mitochondria and the mechanisms involved in somatic cell reprogramming into iPSC and directed reprogramming of iPSCs in terminally differentiated cells. Reprogramming requires changes in cellular characteristics, genomic and epigenetic regulation, as well as major mitochondrial metabolic changes to sustain iPSC self-renewal, pluripotency, and proliferation. Differentiation of autologous iPSC into terminally differentiated β-like cells requires further metabolic adaptation. Many studies have characterized these alterations in signaling pathways required for the generation and differentiation of iPSC; however, very little is known regarding the metabolic shifts that govern pluripotency transition to tissue-specific lineage differentiation. Understanding such metabolic transitions and how to modulate them is essential for the optimization of differentiation processes to ensure safe iPSC-derived cell therapies. In this review, we summarize the current understanding of mitochondrial metabolism during somatic cell reprogramming to iPSCs and the metabolic shift that occurs during directed differentiation into pancreatic β-like cells.
    Keywords:  Diabetes Mellitus; beta cells (β Cells); induced pluripotent stem (iPS) cells; islet transplantation; stem cells
    DOI:  https://doi.org/10.3389/fendo.2023.1236472
  34. Cardiovasc Res. 2023 Oct 31. pii: cvad169. [Epub ahead of print]
    The inhibition of inner mitochondrial fusion in hepatocytes reduces NAFL and improves metabolic profile during obesity by modulating bile acid conjugation.
    Lorenzo Da Dalt, Annalisa Moregola, Monika Svecla, Silvia Pedretti, Francesca Fantini, Mirko Ronzio, Patrizia Uboldi, Diletta Dolfini, Elena Donetti, Andrea Baragetti, Nico Mitro, Luca Scorrano, Giuseppe Danilo Norata.
      BACKGROUND AND AIM: Mitochondria are plastic organelles that continuously undergo biogenesis, fusion, fission, and mitophagy to control cellular energy metabolism, calcium homeostasis, hormones, sterols and bile acids (BAs) synthesis. Here we evaluated how the impairment of mitochondrial fusion in hepatocytes affect diet induced liver steatosis and obesity.METHODS AND RESULTS: Male mice selectively lacking the key protein involved in inner mitochondrial fusion, OPA1, (OPA1ΔHep) on a High Fat Diet (HFD) for 20 weeks. OPA1ΔHep mice were protected from the development of hepatic steatosis and obesity because of reduced lipid absorption; a profile which was accompanied by increased respiratory exchange ratio in vivo, suggesting a preference for carbohydrate in OPA1ΔHep in agreement with the defect in mitochondrial fusion. At the molecular level, this phenotype emerged as a consequence of poor mitochondrial-peroxisome-ER tethering in OPA1 deficient hepatocytes thus impairing bile acid conjugation and therefore its release in the bile, thus impacting lipid absorption from the diet. Concordantly the liver of NAFLD subjects presented an increased expression of OPA1 and of the network of proteins involved in mitochondrial when compared to controls.
    CONCLUSION: Patients with NAFLD present increased expression of proteins involved in mitochondrial fusion in the liver. The selective inhibition of liver mitochondrial fusion observed in hepatocyte OPA1 deficient mice protects mice from HFD-induced metabolic dysfunction by reducing lipid dietary absorption and bile acid secretion as a consequence of reduced liver mitochondria-peroxisome-ER tethering.
    Keywords:  Bile Acids; Dietary Lipid Absorption; Liver; Mitochondria
    DOI:  https://doi.org/10.1093/cvr/cvad169
  35. Cell Rep. 2023 Nov 04. pii: S2211-1247(23)01401-8. [Epub ahead of print]42(11): 113389
    Hepatic palmitoyl-proteomes and acyl-protein thioesterase protein proximity networks link lipid modification and mitochondria.
    Sarah L Speck, Dhaval P Bhatt, Qiang Zhang, Sangeeta Adak, Li Yin, Guifang Dong, Chu Feng, Wei Zhang, M Ben Major, Xiaochao Wei, Clay F Semenkovich.
      Acyl-protein thioesterases 1 and 2 (APT1 and APT2) reverse S-acylation, a potential regulator of systemic glucose metabolism in mammals. Palmitoylation proteomics in liver-specific knockout mice shows that APT1 predominates over APT2, primarily depalmitoylating mitochondrial proteins, including proteins linked to glutamine metabolism. miniTurbo-facilitated determination of the protein-protein proximity network of APT1 and APT2 in HepG2 cells reveals APT proximity networks encompassing mitochondrial proteins including the major translocases Tomm20 and Timm44. APT1 also interacts with Slc1a5 (ASCT2), the only glutamine transporter known to localize to mitochondria. High-fat-diet-fed male mice with dual (but not single) hepatic deletion of APT1 and APT2 have insulin resistance, fasting hyperglycemia, increased glutamine-driven gluconeogenesis, and decreased liver mass. These data suggest that APT1 and APT2 regulation of hepatic glucose metabolism and insulin signaling is functionally redundant. Identification of substrates and protein-protein proximity networks for APT1 and APT2 establishes a framework for defining mechanisms underlying metabolic disease.
    Keywords:  CP: Metabolism; acyl-protein thioesterase 1; acyl-protein thioesterase 2; gluconeogenesis; glutamine; insulin; liver; palmitoylation; proximity labeling
    DOI:  https://doi.org/10.1016/j.celrep.2023.113389
  36. Neurosci Lett. 2023 Nov 04. pii: S0304-3940(23)00501-3. [Epub ahead of print]818 137542
    Transfer of massive mitochondria from astrocytes reduce propofol neurotoxicity.
    Zhan Zhou, Weixin Dai, Tianxiao Liu, Min Shi, Yi Wei, Lifei Chen, Yubo Xie.
      Studies have shown that propofol-induced neurotoxicity is mediated by disruption of mitochondrial fission and fusion, leading to an imbalance in energy supply for developing neurons. Healthy mitochondria released from astrocytes migrate to compromised neurons to mitigate propofol-induced neurotoxicity, yet the precise mechanisms involved require further clarification. In our investigation, primary neurons were incubated with propofol, which decreased ATP synthesis and mitochondrial membrane potential, increased ROS generation and neuronal apoptosis. Notably, astrocytes did not respond to the deleterious effects of propofol. The culture medium of neurons or astrocytes incubated with propofol was collected. It was found that mitochondrial ratio was decreased and mitochondrial function was impaired. Non-contact co-culture of neuro-astrocytes facilitated transcellular mitochondrial transfer in both physiological and propofol interventions, but failed to reverse propofol-induced neurotoxicity. The more pronounced damage to neuronal mitochondria induced by propofol compared to that in astrocytes alludes to secondary injury. Damaged neurons incubated with large, functional extracellular mitochondria derived from astrocytes demonstrates transfer of mitochondria to neurons, effectively reversing propofol-induced neurotoxicity. This discovery presents a novel mitochondrial transfer of neuro-astrocytes crosstalk that contributes to neuroprotection and neurological recovery in neurotoxicity.
    Keywords:  Astrocytes; Mitochondria; Neuron; Neurotoxicity; Propofol
    DOI:  https://doi.org/10.1016/j.neulet.2023.137542
  37. J Biol Chem. 2023 Nov 08. pii: S0021-9258(23)02469-9. [Epub ahead of print] 105441
    Interaction between the mitochondrial adaptor MIRO and the motor adaptor TRAK.
    Elana E Baltrusaitis, Erika E Ravitch, Adam R Fenton, Tania Perez, Erika L F Holzbaur, Roberto Dominguez.
      MIRO (mitochondrial Rho GTPase) consists of two GTPase domains flanking two Ca2+-binding EF-hand domains. A C-terminal transmembrane helix anchors MIRO to the outer mitochondrial membrane, where it functions as a general adaptor for the recruitment of cytoskeletal proteins that control mitochondrial dynamics. One protein recruited by MIRO is TRAK (trafficking kinesin-binding protein), which in turn recruits the microtubule-based motors kinesin-1 and dynein-dynactin. The mechanism by which MIRO interacts with TRAK on the mitochondrial membrane is not well understood. Here, we map and quantitatively characterize the interaction of human MIRO1 and TRAK1 and test its potential regulation by Ca2+ and/or GTP binding to MIRO1. TRAK1 binds MIRO1 with low micromolar affinity. The interaction was mapped to a fragment comprising MIRO1's EF-hands and C-terminal GTPase domain and to a conserved sequence motif within TRAK1 residues 394-431, immediately C-terminal to the Spindly motif. This sequence is sufficient for MIRO1 binding in vitro and is necessary for MIRO1-dependent localization of TRAK1 to mitochondria in cells. MIRO1's EF-hands bind Ca2+ with dissociation constants (KD) of 3.9 μM and 300 nM. This suggests that under cellular conditions one EF-hand may be constitutively bound to Ca2+ whereas the other EF-hand binds Ca2+ in a regulated manner, depending on its local concentration. Yet, the MIRO1-TRAK1 interaction is independent of Ca2+ binding to the EF-hands and of the nucleotide state (GDP or GTP) of the C-terminal GTPase. The interaction is also independent of TRAK1 dimerization, such that a TRAK1 dimer can be expected to bind two MIRO1 molecules on the mitochondrial surface.
    Keywords:  EF-hand; GTPase; Mitochondrial dynamics; calcium; isothermal titration calorimetry (ITC); motor adaptor; mutagenesis
    DOI:  https://doi.org/10.1016/j.jbc.2023.105441
  38. STAR Protoc. 2023 Nov 07. pii: S2666-1667(23)00558-0. [Epub ahead of print]4(4): 102591
    Protocol for isolating mice skeletal muscle myoblasts and myotubes via differential antibody validation.
    Dominique C Stephens, Margaret Mungai, Amber Crabtree, Heather K Beasley, Edgar Garza-Lopez, Larry Vang, Kit Neikirk, Zer Vue, Neng Vue, Andrea G Marshall, Kyrin Turner, Jian-Qiang Shao, Bishnu Sarker, Sandra Murray, Jennifer A Gaddy, Jamaine Davis, Steven M Damo, Antentor O Hinton.
      Isolation of skeletal muscles allows for the exploration of many complex diseases. Here, we present a protocol for isolating mice skeletal muscle myoblasts and myotubes that have been differentiated through antibody validation. We describe steps for collecting and preparing murine skeletal tissue, myoblast cell maintenance, plating, and cell differentiation. We then detail procedures for cell incubation, immunostaining, slide preparation and storage, and imaging for immunofluorescence validation.
    Keywords:  Cell Culture; Cell Isolation; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2023.102591
  39. Biochem Biophys Res Commun. 2023 Nov 01. pii: S0006-291X(23)01304-9. [Epub ahead of print]687 149210
    FUNDC1 collaborates with PINK1 in regulating mitochondrial Fission and compensating for PINK1 deficiency.
    Jing Xu, Zhouyang Deng, Shuai Shang, Caifang Wang, Hailong Han.
      Parkinson's disease is presently thought to have its molecular roots in the alteration of PINK1-mediated mitophagy and mitochondrial dynamics. Finding new suppressors of the pathway is essential for developing cutting-edge treatment approaches. Our study shows that FUNDC1 suppressed PINK1 mutant phenotypes in Drosophila. The restoration of PINK1-deficient phenotypes through FUNDC1 is not reliant on its LC3-binding motif Y (18)L (21) or autophagy-related pathway. Moreover, the absence of Drp1 affects the phenotypic restoration of PINK1 mediated by FUNDC1 in flies. In summary, our findings have unveiled a fresh mechanism through which FUNDC1 compensates for the loss of PINK1, operating independently of autophagy but exerting its influence via interaction with Drp1.
    Keywords:  Autophagy receptor; Drp1; Mitochondrial dynamics; PD; Ubiquitin-independent mitophagy
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149210
  40. Orphanet J Rare Dis. 2023 Nov 09. 18(1): 348
    International Undiagnosed Diseases Programs (UDPs): components and outcomes.
    Ela Curic, Lisa Ewans, Ryan Pysar, Fulya Taylan, Lorenzo D Botto, Ann Nordgren, William Gahl, Elizabeth Emma Palmer.
      Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program.
    Keywords:  Genomics; Rare diseases; Undiagnosed Diseases Programs
    DOI:  https://doi.org/10.1186/s13023-023-02966-1
  41. Life Sci. 2023 Nov 08. pii: S0024-3205(23)00892-5. [Epub ahead of print] 122257
    Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview.
    Eman E Alshial, Muhammad Idris Abdulghaney, Al-Hassan Soliman Wadan, Mohamed Abdelfatah Abdellatif, Nada E Ramadan, Aya Muhammed Suleiman, Nahla Waheed, Maha Abdellatif, Haitham S Mohammed.
      Mitochondria play a vital role in the nervous system, as they are responsible for generating energy in the form of ATP and regulating cellular processes such as calcium (Ca2+) signaling and apoptosis. However, mitochondrial dysfunction can lead to oxidative stress (OS), inflammation, and cell death, which have been implicated in the pathogenesis of various neurological disorders. In this article, we review the main functions of mitochondria in the nervous system and explore the mechanisms related to mitochondrial dysfunction. We discuss the role of mitochondrial dysfunction in the development and progression of some neurological disorders including Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), depression, and epilepsy. Finally, we provide an overview of various current treatment strategies that target mitochondrial dysfunction, including pharmacological treatments, phototherapy, gene therapy, and mitotherapy. This review emphasizes the importance of understanding the role of mitochondria in the nervous system and highlights the potential for mitochondrial-targeted therapies in the treatment of neurological disorders. Furthermore, it highlights some limitations and challenges encountered by the current therapeutic strategies and puts them in future perspective.
    Keywords:  Alzheimer's disease; Depression; Epilepsy; Mitochondrial dysfunction; Multiple sclerosis; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.lfs.2023.122257
  42. Cell Rep Methods. 2023 Nov 02. pii: S2667-2375(23)00290-4. [Epub ahead of print] 100626
    Dual stop codon suppression in mammalian cells with genomically integrated genetic code expansion machinery.
    Birthe Meineke, Johannes Heimgärtner, Rozina Caridha, Matthias F Block, Kyle J Kimler, Maria F Pires, Michael Landreh, Simon J Elsässer.
      Stop codon suppression using dedicated tRNA/aminoacyl-tRNA synthetase (aaRS) pairs allows for genetically encoded, site-specific incorporation of non-canonical amino acids (ncAAs) as chemical handles for protein labeling and modification. Here, we demonstrate that piggyBac-mediated genomic integration of archaeal pyrrolysine tRNA (tRNAPyl)/pyrrolysyl-tRNA synthetase (PylRS) or bacterial tRNA/aaRS pairs, using a modular plasmid design with multi-copy tRNA arrays, allows for homogeneous and efficient genetically encoded ncAA incorporation in diverse mammalian cell lines. We assess opportunities and limitations of using ncAAs for fluorescent labeling applications in stable cell lines. We explore suppression of ochre and opal stop codons and finally incorporate two distinct ncAAs with mutually orthogonal click chemistries for site-specific, dual-fluorophore labeling of a cell surface receptor on live mammalian cells.
    Keywords:  CP: Biotechnology; CP: Molecular biology; Genetic code expansion; amber suppression; bioorthogonal labeling; click chemistry; mammalian cell culture; non-canonical amino acids; random genomic integration; stop codon suppression; unnatural amino acids
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100626
  43. Nat Cell Biol. 2023 Nov;25(11): 1564-1565
    Sperm bud mitochondria to adjust the numbers.
    Diane C Shakes.
      
    DOI:  https://doi.org/10.1038/s41556-023-01255-0
  44. JIMD Rep. 2023 Nov;64(6): 453-459
    Patients with primary carnitine deficiency treated with L-carnitine are alive and doing well-A 10-year follow-up in the Faroe Islands.
    Rannvá K Abrahamsen, Allan M Lund, Jan Rasmussen.
      Primary carnitine deficiency (PCD) can be lethal. Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for β-oxidation. The reported prevalence of PCD in the Faroe Islands of 1:300 is the highest in the world. The Faroese PCD patient cohort has been closely monitored and we now report results from a 10-year follow-up study of 139 PCD patients. Four patients have died of natural causes since diagnosis. There were no signs of cardiac complications related to PCD. 70.5% reported an effect of L-carnitine treatment. 33.7% reported current symptoms with fatigue and low stamina being the most common. 65.1% had experienced side effects during L-carnitine treatment. Most common side effects were fish odor, abdominal pain, and diarrhea. The overall mean L-carnitine dosage was 66.3 mg/kg/day. Free p-carnitine was similar between male and female patients on L-carnitine-18.6 and 18.8 μmol/L, respectively. L-carnitine supplementation seems to be a safe and effective treatment when suffering from PCD. PCD patients in the Faroe Islands are alive and doing well more than 10 years after diagnosis.
    Keywords:  Faroe Islands; inherited metabolic disease; neonatal screening; primary carnitine deficiency; sudden death
    DOI:  https://doi.org/10.1002/jmd2.12383
  45. Free Radic Biol Med. 2023 Nov 02. pii: S0891-5849(23)01076-6. [Epub ahead of print]209(Pt 2): 355-365
    From workout to molecular switches: How does skeletal muscle produce, sense, and transduce subcellular redox signals?
    Carlos Henriquez-Olguin, Roberto Meneses-Valdes, Paraskevi Kritsiligkou, Eduardo Fuentes-Lemus.
      Skeletal muscle is crucial for maintaining human health and overall quality of life. Acute exercise introduces a multifaceted intracellular stress, with numerous post-translational modifications believed to underpin the health benefits of sustained exercise training. Reactive oxygen species (ROS) are posited to serve as second messengers, triggering cytoprotective adaptations such as the upregulation of enzymatic scavenger systems. However, a significant knowledge gap exists between the generation of oxidants in muscle and the exact mechanisms driving muscle adaptations. This review delves into the current research on subcellular redox biochemistry and its role in the physiological adaptations to exercise. We propose that the subcellular regulation of specific redox modifications is key to ensuring specificity in the intracellular response.
    Keywords:  Exercise training; Hydrogen peroxide; Mitochondria; Redox signaling; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.10.404
  46. Genet Med. 2023 Oct 31. pii: S1098-3600(23)01029-8. [Epub ahead of print] 101013
    De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.
    Theresa Brunet, Benedikt Zott, Victoria Lieftüchter, Dominic Lenz, Axel Schmidt, Philipp Peters, Robert Kopajtich, Malin Zaddach, Hanna Zimmermann, Irina Hüning, Diana Ballhausen, Christian Staufner, Alyssa Bianzano, Joanne Hughes, Robert W Taylor, Robert McFarland, Anita Devlin, Mihaela Mihaljević, Nina Barišić, Meino Rohlfs, Sibylle Wilfling, Neal Sondheimer, Stacy Hewson, Nikolaos M Marinakis, Konstantina Kosma, Joanne Traeger-Synodinos, Miriam Elbracht, Matthias Begemann, Sonja Trepels-Kottek, Dimah Hasan, Marcello Scala, Valeria Capra, Federico Zara, Amelie T van der Ven, Joenna Driemeyer, Christian Apitz, Johannes Krämer, Alanna Strong, Hakon Hakonarson, Deborah Watson, Johannes A Mayr, Holger Prokisch, Thomas Meitinger, Ingo Borggraefe, Juliane Spiegler, Ivo Baric, Marco Paolini, Lucia Gerstl, Matias Wagner.
      PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease (MMD). Case reports have also implicated specific variants in RNF213 with an early-onset form of MMD with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations.METHODS: Patients were identified through reanalysis of exome sequencing (ES) data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient derived fibroblasts.
    RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the RING domain. Individuals presented either with early-onset stroke (n=11) or with Leigh syndrome (n=3). No genotype-phenotype correlation could be established. Proteomics using patient derived fibroblasts revealed no significant differences between clinical subgroups. 3D-modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting Zinc-binding suggesting a gain-of-function or dominant negative effect.
    CONCLUSIONS: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting Zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.
    Keywords:  RNF213; exome sequencing; leigh syndrome; moyamoya; stroke
    DOI:  https://doi.org/10.1016/j.gim.2023.101013
  47. Arterioscler Thromb Vasc Biol. 2023 Nov 09.
    Physical Contacts Between Mitochondria and WPBs Participate in WPB Maturation.
    Jing Ma, Zhenhua Hao, Yudong Zhang, Liuju Li, Xiaoshuai Huang, Yu Wang, Liangyi Chen, Ge Yang, Wei Li.
      BACKGROUND: Weibel-Palade bodies (WPBs) are endothelial cell-specific cigar-shaped secretory organelles containing various biologically active molecules. WPBs play crucial roles in thrombosis, hemostasis, angiogenesis, and inflammation. The main content of WPBs is the procoagulant protein vWF (von Willebrand factor). Physical contacts and functional cross talk between mitochondria and other organelles have been demonstrated. Whether an interorganellar connection exists between mitochondria and WPBs is unknown.METHODS: We observed physical contacts between mitochondria and WPBs in human umbilical vein endothelial cells by electron microscopy and living cell confocal microscopy. We developed an artificial intelligence-assisted method to quantify the duration and length of organelle contact sites in live cells.
    RESULTS: We found there existed physical contacts between mitochondria and WPBs. Disruption of mitochondrial function affected the morphology of WPBs. Furthermore, we found that Rab3b, a small GTPase on the WPBs, was enriched at the mitochondrion-WPB contact sites. Rab3b deficiency reduced interaction between the two organelles and impaired the maturation of WPBs and vWF multimer secretion.
    CONCLUSIONS: Our results reveal that Rab3b plays a crucial role in mediating the mitochondrion-WPB contacts, and that mitochondrion-WPB coupling is critical for the maturation of WPBs in vascular endothelial cells.
    Keywords:  Weibel-Palade body; endothelial cells; mitochondrion; organelle interaction; von Willebrand factor
    DOI:  https://doi.org/10.1161/ATVBAHA.123.319939
  48. Genome Med. 2023 Nov 09. 15(1): 94
    Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.
    Alistair T Pagnamenta, Carme Camps, Edoardo Giacopuzzi, John M Taylor, Mona Hashim, Eduardo Calpena, Pamela J Kaisaki, Akiko Hashimoto, Jing Yu, Edward Sanders, Ron Schwessinger, Jim R Hughes, Gerton Lunter, Helene Dreau, Matteo Ferla, Lukas Lange, Yesim Kesim, Vassilis Ragoussis, Dimitrios V Vavoulis, Holger Allroggen, Olaf Ansorge, Christian Babbs, Siddharth Banka, Benito Baños-Piñero, David Beeson, Tal Ben-Ami, David L Bennett, Celeste Bento, Edward Blair, Charlotte Brasch-Andersen, Katherine R Bull, Holger Cario, Deirdre Cilliers, Valerio Conti, E Graham Davies, Fatima Dhalla, Beatriz Diez Dacal, Yin Dong, James E Dunford, Renzo Guerrini, Adrian L Harris, Jane Hartley, Georg Hollander, Kassim Javaid, Maureen Kane, Deirdre Kelly, Dominic Kelly, Samantha J L Knight, Alexandra Y Kreins, Erika M Kvikstad, Craig B Langman, Tracy Lester, Kate E Lines, Simon R Lord, Xin Lu, Sahar Mansour, Adnan Manzur, Reza Maroofian, Brian Marsden, Joanne Mason, Simon J McGowan, Davide Mei, Hana Mlcochova, Yoshiko Murakami, Andrea H Németh, Steven Okoli, Elizabeth Ormondroyd, Lilian Bomme Ousager, Jacqueline Palace, Smita Y Patel, Melissa M Pentony, Chris Pugh, Aboulfazl Rad, Archana Ramesh, Simone G Riva, Irene Roberts, Noémi Roy, Outi Salminen, Kyleen D Schilling, Caroline Scott, Arjune Sen, Conrad Smith, Mark Stevenson, Rajesh V Thakker, Stephen R F Twigg, Holm H Uhlig, Richard van Wijk, Barbara Vona, Steven Wall, Jing Wang, Hugh Watkins, Jaroslav Zak, Anna H Schuh, Usha Kini, Andrew O M Wilkie, Niko Popitsch, Jenny C Taylor.
      BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome.METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants.
    RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving.
    CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.
    Keywords:  Bioinformatics pipeline development; Clinical impact; Diagnostic yield; Genome sequencing; Non-coding; Pipeline optimisation; Rare diseases; Splice site variant; Structural variant
    DOI:  https://doi.org/10.1186/s13073-023-01240-0
  49. Nat Cell Biol. 2023 Nov;25(11): 1625-1636
    Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.
    Peng Liu, Jing Shi, Danli Sheng, Wenqing Lu, Jie Guo, Lei Gao, Xiaoqing Wang, Shaofeng Wu, Yanwen Feng, Dashan Dong, Xiaoshuai Huang, Hongyun Tang.
      Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies have shed light on the process of discarding damaged mitochondria, how mitochondria are exported and the functions of mitochondrial release remain largely unclear. Here we describe mitopherogenesis, a formerly unknown process that specifically secretes mitochondria through a unique extracellular vesicle termed a 'mitopher'. We observed that during sperm development in male Caenorhabditis elegans, healthy mitochondria are exported out of the spermatids through mitopherogenesis and each of the generated mitophers harbours only one mitochondrion. In mitopherogenesis, the plasma membrane first forms mitochondrion-embedding outward buds, which then promptly bud off and thereby result in the generation of mitophers. Mechanistically, extracellular protease signalling in the testis triggers mitopher formation from spermatids, which is partially mediated by the tyrosine kinase SPE-8. Moreover, mitopherogenesis requires normal microfilament dynamics, whereas myosin VI antagonizes mitopher generation. Strikingly, our three-dimensional electron microscopy analyses indicate that mitochondrial quantity requires precise modulation during sperm development, which is critically mediated by mitopherogenesis. Inhibition of mitopherogenesis causes accumulation of mitochondria in sperm, which may lead to sperm motility and fertility defects. Our findings identify mitopherogenesis as a previously undescribed process for mitochondria-specific ectocytosis, which may represent a fundamental branch of mechanisms underlying mitochondrial quantity control to regulate cell functions during development.
    DOI:  https://doi.org/10.1038/s41556-023-01264-z
  50. Cell Death Dis. 2023 Nov 10. 14(11): 732
    SIRT1 inhibits mitochondrial hyperfusion associated mito-bulb formation to sensitize oral cancer cells for apoptosis in a mtROS-dependent signalling pathway.
    Srimanta Patra, Amruta Singh, Prakash P Praharaj, Nitish K Mohanta, Mrutyunjay Jena, Birija S Patro, Ali Abusharha, Shankargouda Patil, Sujit K Bhutia.
      SIRT1 (NAD-dependent protein deacetylase sirtuin-1), a class III histone deacetylase acting as a tumor suppressor gene, is downregulated in oral cancer cells. Non-apoptotic doses of cisplatin (CDDP) downregulate SIRT1 expression advocating the mechanism of drug resistance. SIRT1 downregulation orchestrates inhibition of DNM1L-mediated mitochondrial fission, subsequently leading to the formation of hyperfused mitochondrial networks. The hyperfused mitochondrial networks preserve the release of cytochrome C (CYCS) by stabilizing the mitochondrial inner membrane cristae (formation of mitochondrial nucleoid clustering mimicking mito-bulb like structures) and reducing the generation of mitochondrial superoxide to inhibit apoptosis. Overexpression of SIRT1 reverses the mitochondrial hyperfusion by initiating DNM1L-regulated mitochondrial fission. In the overexpressed cells, inhibition of mitochondrial hyperfusion and nucleoid clustering (mito-bulbs) facilitates the cytoplasmic release of CYCS along with an enhanced generation of mitochondrial superoxide for the subsequent induction of apoptosis. Further, low-dose priming with gallic acid (GA), a bio-active SIRT1 activator, nullifies CDDP-mediated apoptosis inhibition by suppressing mitochondrial hyperfusion. In this setting, SIRT1 knockdown hinders apoptosis activation in GA-primed oral cancer cells. Similarly, SIRT1 overexpression in the CDDP resistance oral cancer-derived polyploid giant cancer cells (PGCCs) re-sensitizes the cells to apoptosis. Interestingly, synergistically treated with CDDP, GA induces apoptosis in the PGCCs by inhibiting mitochondrial hyperfusion.
    DOI:  https://doi.org/10.1038/s41419-023-06232-x
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