bims-mitdis 2024-12-08 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2024–12–08
33 papers selected by
Catalina Vasilescu, Helmholz Munich

OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.
Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.
Comprehensive review of mitochondrial nephropathy-a renal phenotype in mitochondrial disease: causative genes, clinical and pathological features, diagnosis, prognosis, and treatment.
Coordination of cytochrome bc1 complex assembly at MICOS.
Structural Basis for the Pathogenicity of Parkin Catalytic Domain Mutants.
OCIAD1 and prohibitins regulate the stability of the TIM23 protein translocase.
Expanded-Access Use of Elamipretide Improves Quality of Life in Patients With Rare Mitochondrial Disorders Characterized by Ophthalmic Symptoms: A Case Series.
Purification of mitochondria from skeletal muscle tissue for transcriptomic analyses reveals localization of nuclear-encoded noncoding RNAs.
Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex.
Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue.
RMND1 Mutation Case Report and Literature Review.
SURF1 Deficiency: Expanding on Disease Phenotype and Assessing Disease Burden by Describing Clinical and Biochemical Phenotype.
Mitochondrial DNA Depletion Syndromes Gene Panel versus Clinical Exome Sequencing in Children with Suspected Mitochondrial Hepatopathies.
Toward a Quadruplet Codon Mitochondrial Genetic Code.
Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
Mitochondrial metabolism and redox signaling.
Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells.
Respiratory complex II acting as a homeostatic regulatory sensor.
An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy.
Mitochondrial Transplantation in Brain Disorders: Achievements, Methods, and Challenges.
Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α.
SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia.
Homozygous Microdeletion Involving Exon 1 of ERCC8 and NDUFAF2 With Uniparental Isodisomy of Chromosome 5.
Identification of rare disease genes as drivers of common diseases through tissue-specific gene regulatory networks.
Understanding genetic variants in context.
Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation.
A fully automated morphological analysis of yeast mitochondria from wide-field fluorescence images.
Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.
Pioneering Advances and Innovative Applications of Mesoporous Carriers for Mitochondria-Targeted Therapeutics.
Mitochondrial-targeted liposome-based drug delivery - Therapeutic potential and challenges.
Effective data visualization strategies in untargeted metabolomics.
A Novel NDUFV2 Variant in an Asymptomatic Adolescent Girl with Progressive Cavitating Leukoencephalopathy.
Missense variants in the TRPMr7 α-kinase domain are associated with recurrent pediatric acute liver failure.

Cell Death Dis. 2024 Nov 30. 15(11): 870

OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.

J Macuada, I Molina-Riquelme, G Vidal, N Pérez-Bravo, C Vásquez-Trincado, G Aedo, D Lagos, P Yu-Wai-Man, R Horvath, T J Rudge, B Cartes-Saavedra, V Eisner.

Optic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on nucleoid distribution using high-resolution confocal microscopy. We applied a novel model incorporating the mitochondrial context, separating nucleoid distribution into the array in the mitochondrial population and intramitochondrial longitudinal distribution. Opa1-null cells showed decreased mtDNA levels and nucleoid abundance. Also, loss of Opa1 led to an altered distribution of nucleoids in the mitochondrial population, loss of cristae periodicity, and altered nucleoids to cristae proximity partly rescued by OPA1 isoform 1. Overexpression of WT OPA1 or ADOA-causing mutants c.870+5 G > A or c.2713 C > T in WT cells, showed perturbed nucleoid array in the mitochondria population associated with cristae disorganization, which was partly reproduced in Skeletal muscle-derived fibroblasts from ADOA patients harboring the same mutants. Opa1-null and cells overexpressing ADOA mutants accumulated mitochondria without nucleoids. Interestingly, intramitochondrial nucleoid distribution was only altered in Opa1-null cells. Altogether, our results highlight the relevance of OPA1 in nucleoid distribution in the mitochondrial landscape and at a single-organelle level and shed light on new components of ADOA etiology.

DOI: https://doi.org/10.1038/s41419-024-07165-9
Aging Cell. 2024 Dec 04. e14386

Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.

Richie P Goulding, Braeden T Charlton, Ellen A Breedveld, Matthijs van der Laan, Anne R Strating, Wendy Noort, Aryna Kolodyazhna, Brent Appelman, Michèle van Vugt, Anita E Grootemaat, Nicole N van der Wel, Jos J de Koning, Frank W Bloemers, Rob C I Wüst.

  Ageing substantially impairs skeletal muscle metabolic and physical function. Skeletal muscle mitochondrial health is also impaired with ageing, but the role of skeletal muscle mitochondrial fragmentation in age-related functional decline remains imprecisely characterized. Here, using a cross-sectional study design, we performed a detailed comparison of skeletal muscle mitochondrial characteristics in relation to in vivo markers of exercise capacity between young and middle-aged individuals. Despite similar overall oxidative phosphorylation capacity (young: 99 ± 17 vs. middle-aged: 99 ± 27 pmol O2.s-1.mg-1, p = 0.95) and intermyofibrillar mitochondrial density (young: 5.86 ± 0.57 vs. middle-aged: 5.68 ± 1.48%, p = 0.25), older participants displayed a more fragmented intermyofibrillar mitochondrial network (young: 1.15 ± 0.17 vs. middle-aged: 1.55 ± 0.15 A.U., p < 0.0001), a lower mitochondrial cristae density (young: 23.40 ± 7.12 vs. middle-aged: 13.55 ± 4.10%, p = 0.002) and a reduced subsarcolemmal mitochondrial density (young: 22.39 ± 6.50 vs. middle-aged: 13.92 ± 4.95%, p = 0.005). Linear regression analysis showed that 87% of the variance associated with maximal oxygen uptake could be explained by skeletal muscle mitochondrial fragmentation and cristae density alone, whereas subsarcolemmal mitochondrial density was positively associated with the capacity for oxygen extraction during exercise. Intramuscular lipid accumulation was positively associated with mitochondrial fragmentation and negatively associated with cristae density. Collectively, our work highlights the critical role of skeletal muscle mitochondria in age-associated declines in physical function.

Keywords:  ageing; maximal oxygen uptake; mitochondrial morphology; mitochondrial respiration; skeletal muscle

DOI:  https://doi.org/10.1111/acel.14386
Clin Exp Nephrol. 2024 Dec 03.

Comprehensive review of mitochondrial nephropathy-a renal phenotype in mitochondrial disease: causative genes, clinical and pathological features, diagnosis, prognosis, and treatment.

Toshiyuki Imasawa, Kei Murayama, Daishi Hirano, Kandai Nozu.

  Mitochondrial nephropathy is a genetic renal disease characterized by oxidative phosphorylation abnormalities in the mitochondrial respiratory chain in kidney cells, caused by pathogenic gene variants located on mitochondrial or nuclear DNA. Recent advancements in genetic diagnostic techniques and their widespread adoption have led to the identification of various genes associated with mitochondrial nephropathy. This review investigates the causative genes and clinicopathological features of mitochondrial nephropathy, including the various phenotypes and associated complications, and suggests potential pathogenic mechanisms. Furthermore, the diagnostic methods of the disease are explained with particular emphasis on characteristic pathological findings and genetic analysis. We also analyze the available long-term observational prognostic data. Although there is currently no evidence-based treatment for mitochondrial nephropathy, an overview of the existing treatment options is discussed, including future expectations. The choice of renal replacement therapy in cases with progression to end-stage renal disease has also been discussed. Overall, this review highlights the importance of raising awareness about mitochondrial nephropathy and establishing appropriate diagnostic systems to facilitate rapid and effective treatment.

Keywords:  Focal segmental glomerulosclerosis; Granular swollen epithelial cell; Mitochondria; Mitochondrial nephropathy; Tubulointerstitial nephropathy

DOI:  https://doi.org/10.1007/s10157-024-02554-y
EMBO Rep. 2024 Dec 02.

Coordination of cytochrome bc1 complex assembly at MICOS.

Ralf M Zerbes, Lilia Colina-Tenorio, Maria Bohnert, Karina von der Malsburg, Christian D Peikert, Carola S Mehnert, Inge Perschil, Rhena F U Klar, Rinse de Boer, Anita Kram, Ida van der Klei, Silke Oeljeklaus, Bettina Warscheid, Heike Rampelt, Martin van der Laan.

  The boundary and cristae domains of the mitochondrial inner membrane are connected by crista junctions. Most cristae membrane proteins are nuclear-encoded and inserted by the mitochondrial protein import machinery into the inner boundary membrane. Thus, they must overcome the diffusion barrier imposed by crista junctions to reach their final location. Here, we show that respiratory chain complexes and assembly intermediates are physically connected to the mitochondrial contact site and cristae organizing system (MICOS) that is essential for the formation and stability of crista junctions. We identify the inner membrane protein Mar26 (Fmp10) as a determinant in the biogenesis of the cytochrome bc1 complex (complex III). Mar26 couples a Rieske Fe/S protein-containing assembly intermediate to MICOS. Our data indicate that Mar26 maintains an assembly-competent Rip1 pool at crista junctions where complex III maturation likely occurs. MICOS facilitates efficient Rip1 assembly by recruiting complex III assembly intermediates to crista junctions. We propose that MICOS, via interaction with assembly factors such as Mar26, contributes to the spatial and temporal coordination of respiratory chain biogenesis.

Keywords:   bc 1 Complex; Cristae; MICOS; Mitochondria; Respiratory Chain

DOI:  https://doi.org/10.1038/s44319-024-00336-x
J Biol Chem. 2024 Dec 02. pii: S0021-9258(24)02553-5. [Epub ahead of print] 108051

Structural Basis for the Pathogenicity of Parkin Catalytic Domain Mutants.

Julian P Wagner, Véronique Sauvé, Anshu Saran, Kalle Gehring.

Mutations in the E3 ubiquitin ligase parkin cause a familial form of Parkinson's disease (PD). Parkin and the mitochondrial kinase PINK1 assure quality control of mitochondria through selective autophagy of mitochondria (mitophagy). Whereas numerous parkin mutations have been functionally and structurally characterized, several PD mutations found in the catalytic Rcat domain of parkin remain poorly understood. Here, we characterize two pathogenic Rcat mutants, T415N and P437L. We demonstrate that both mutants exhibit impaired activity using autoubiquitination and ubiquitin vinyl sulfone assays. We determine the minimal ubiquitin binding segment and show that both mutants display impaired binding of ubiquitin charged on the E2 enzyme. Finally, we use AlphaFold 3 to predict a model of the phospho-parkin:phospho-ubiquitin:ubiquitin-charged E2 complex. The model shows the repressor-element of parkin (REP) and the N-terminal residues of the catalytic domain form a helix to position ubiquitin for transfer from the E2 to parkin. Our results rationalize the pathogenicity of the parkin mutations and deepen our understanding of the active parkin-E2∼Ub complex.

DOI: https://doi.org/10.1016/j.jbc.2024.108051
Cell Rep. 2024 Dec 03. pii: S2211-1247(24)01389-5. [Epub ahead of print]43(12): 115038

OCIAD1 and prohibitins regulate the stability of the TIM23 protein translocase.

Praveenraj Elancheliyan, Klaudia K Maruszczak, Remigiusz Adam Serwa, Till Stephan, Ahmet Sadik Gulgec, Mayra A Borrero-Landazabal, Sonia Ngati, Aleksandra Gosk, Stefan Jakobs, Michal Wasilewski, Agnieszka Chacinska.

  Mitochondrial proteins are transported and sorted to the matrix or inner mitochondrial membrane by the presequence translocase TIM23. In yeast, this essential and highly conserved machinery is composed of the core subunits Tim23 and Tim17. The architecture, assembly, and regulation of the human TIM23 complex are poorly characterized. The human genome encodes two paralogs, TIMM17A and TIMM17B. Here, we describe an unexpected role of the ovarian cancer immunoreactive antigen domain-containing protein 1 (OCIAD1) and the prohibitin complex in the biogenesis of human TIM23. Prohibitins were required to stabilize both the TIMM17A- and TIMM17B-containing variants of the translocase. Interestingly, OCIAD1 assembled with the prohibitin complex to protect the TIMM17A variant from degradation by the YME1L protease. The expression of OCIAD1 was in turn regulated by the status of the TIM23 complex. We postulate that OCIAD1 together with prohibitins constitute a regulatory axis that differentially regulates variants of human TIM23.

Keywords:  CP: Cell biology; OCIAD1; TIM23 translocase; biogenesis; mitochondria; prohibitin

DOI:  https://doi.org/10.1016/j.celrep.2024.115038
Clin Case Rep. 2024 Dec;12(12): e9591

Expanded-Access Use of Elamipretide Improves Quality of Life in Patients With Rare Mitochondrial Disorders Characterized by Ophthalmic Symptoms: A Case Series.

Sharique Ansari, Mary Kay Koenig.

  This case series presents the use of elamipretide in two patients with different progressive mitochondrial disorders (chronic progressive external ophthalmoplegia [CPEO] plus and neuropathy, ataxia, and retinitis pigmentosa [NARP] syndrome) characterized by ophthalmic traits. Elamipretide was well tolerated and both patients demonstrated improvement in symptoms while on therapy.

Keywords:  CPEO; Cardiolipin; Elamipretide; NARP syndrome; mitochondrial disease

DOI:  https://doi.org/10.1002/ccr3.9591
FASEB J. 2024 Dec 15. 38(23): e70223

Purification of mitochondria from skeletal muscle tissue for transcriptomic analyses reveals localization of nuclear-encoded noncoding RNAs.

Jessica Silver, Adam J Trewin, Stella Loke, Larry Croft, Mark Ziemann, Megan Soria, Hayley Dillon, Søren Nielsen, Séverine Lamon, Glenn D Wadley.

Mitochondria are central to cellular function, particularly in metabolically active tissues such as skeletal muscle. Nuclear-encoded RNAs typically localize within the nucleus and cytosol but a small population may also translocate to subcellular compartments such as mitochondria. We aimed to investigate the nuclear-encoded RNAs that localize within the mitochondria of skeletal muscle cells and tissue. Intact mitochondria were isolated via immunoprecipitation (IP) followed by enzymatic treatments (RNase-A and proteinase-K) optimized to remove transcripts located exterior to mitochondria, making it amenable for high-throughput transcriptomic sequencing. Small RNA sequencing libraries were successfully constructed from as little as 1.8 ng mitochondrial RNA input. Small RNA sequencing of mitochondria from rat myoblasts revealed the enrichment of over 200 miRNAs. Whole-transcriptome RNA sequencing of enzymatically purified mitochondria isolated by IP from skeletal muscle tissue showed a striking similarity in the degree of purity compared to mitoplast preparations which lack an outer mitochondrial membrane. In summary, we describe a novel, powerful sequencing approach applicable to animal and human tissues and cells that can facilitate the discovery of nuclear-encoded RNA transcripts localized within skeletal muscle mitochondria.

DOI: https://doi.org/10.1096/fj.202401618R
Nat Commun. 2024 Dec 04. 15(1): 10559

Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex.

Ralf Steinhilper, Linda Boß, Sven-A Freibert, Vinzent Schulz, Nils Krapoth, Susann Kaltwasser, Roland Lill, Bonnie J Murphy.

Iron-sulfur (FeS) protein biogenesis in eukaryotes begins with the de novo assembly of [2Fe-2S] clusters by the mitochondrial core iron-sulfur cluster assembly (ISC) complex. This complex comprises the scaffold protein ISCU2, the cysteine desulfurase subcomplex NFS1-ISD11-ACP1, the allosteric activator frataxin (FXN) and the electron donor ferredoxin-2 (FDX2). The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a 'distal' conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a 'proximal' conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex.

DOI: https://doi.org/10.1038/s41467-024-54585-4
Cell Metab. 2024 Dec 03. pii: S1550-4131(24)00418-2. [Epub ahead of print]36(12): 2491-2492

Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue.

Andreas Carlström, Martin Ott.

Mitochondrial energy conversion supplies cellular energy but can also provide heat in brown adipose tissue (BAT). In a recent study, Shin and Latorre-Muro et al.1 show that respiratory supercomplexes in BAT are remodeled during cold to provide a tighter coupling, revealing a novel, physiologically important role for these supramolecular assemblies.

DOI: https://doi.org/10.1016/j.cmet.2024.10.022
Mol Syndromol. 2024 Dec;15(6): 487-494

RMND1 Mutation Case Report and Literature Review.

Harun Bayrak, Abdullah Sezer, Mustafa Kılıç.

   Introduction: Mutations in the RMND1 gene that cause defects in the mitochondrial respiratory chain result in a highly variable phenotypic presentation. The protein required for meiotic nuclear division 1 homolog (RMND1) is localized to the inner mitochondrial membrane and is encoded by the nuclear genome.
Case Presentation: We report a new patient from a consanguineous family who was severely affected by a previously described combined oxidative phosphorylation deficiency 11 and was treated rapidly due to early diagnosis.
Methods: We also included patients with RMND1 mutation in the literature. We analyzed the epidemiological, clinical, laboratory, and genetic data of a total of 49 patients (98 alleles) in the literature, including our patient. We summarized all previously published patients and focused on the importance of early diagnosis.
Results: The most common variant in patients with RMND1 mutation was c.713A>G (p.Asn238Ser). Mortality was significantly lower in patients with homozygous and compound heterozygous c.713A>G (p.Asn238Ser) mutations (p < 0.001). The second most common mutation was c1349G>C (p.*450Serext*31), which was reported in 11 patients (22.4%). Cardiac involvement and mortality were more common in patients with homozygous c.1349G>C (p.*450Serext*32) mutation (p = 0.008 and 0.008, respectively).
Conclusion: In this study, the effect of cardiac involvement on mortality in RMND1 mutation was shown for the first time. We reported that mortality was lower in the c.713A>G (p.Asn238Ser) mutation. Furthermore, mortality was more common in the c.1349G>C (p.*450Serext*32) mutation. These findings have not been previously reported in the literature. They are reported for the first time in this study.

Keywords:  Combined oxidative phosphorylation deficiency; Developmental delay; Mitochondrial disease; RMND1 gene; Sensorineural hearing loss

DOI:  https://doi.org/10.1159/000538930
Am J Med Genet A. 2024 Dec 05. e63947

SURF1 Deficiency: Expanding on Disease Phenotype and Assessing Disease Burden by Describing Clinical and Biochemical Phenotype.

Saima Kayani, Victor Daescu, Hamza Dahshi, Souad Messahel, Kasey Woleban, Berge A Minassian, Qinglan Ling, Steven J Gray.

  Leigh syndrome, a severe neurological disorder is commonly caused by homozygous or bi-allelic pathogenic variants in the SURF1 gene. SURF1 deficiency leads to dysfunction of Cytochrome C Oxidase (COX) activity, which is crucial for mitochondrial oxidative phosphorylation. Understanding COX activity's correlation with disease severity is essential for developing SURF1 Leigh Syndrome biomarkers. This study assesses the disease burden in SURF1 Leigh Syndrome and evaluates COX activity as a treatment biomarker. We reviewed records and questionnaires from 17 individuals, classifying them into phenotypic and genotypic groups. We compared COX activity assays in patient fibroblasts to age-matched controls, clinical data, and neuroimaging findings. Patient COX activity was at most 50% of controls, averaging 32% (p < 0.001). Common clinical features included brainstem abnormalities (93.3%), motor regression (92.3%), bi-allelic heterozygous SURF1 variants (88.2%), and delayed growth/development (35.7%). Homozygous and heterozygous nonsense/frameshift variants showed more severe phenotypes (p = 0.008) and more MRI abnormalities (p = 0.005). Significant COX activity reduction is linked to SURF1 Leigh Syndrome, with genotype influencing disease severity. Clinical and neuroimaging correlations show potential for prognostic indicators. This study lays the groundwork for future research and clinical application of COX activity as a SURF1 Leigh Syndrome biomarker.

Keywords:  Leigh syndrome; SURF1 gene; biomarkers; cytochrome C oxidase; mitochondrial disorders; neuroimaging

DOI:  https://doi.org/10.1002/ajmg.a.63947
Mol Syndromol. 2024 Dec;15(6): 450-463

Mitochondrial DNA Depletion Syndromes Gene Panel versus Clinical Exome Sequencing in Children with Suspected Mitochondrial Hepatopathies.

Neslihan Doğulu, Engin Köse, Serdar Ceylaner, Çiğdem Seher Kasapkara, Ayşe Ergul Bozaci, Ummuhan Oncul, Fatma Tuba Eminoğlu.

   Introduction: Mitochondrial DNA depletion syndromes (MDDSs) are a group of clinically and genetically heterogeneous disorders. In the present study, we aimed to investigate the frequency of MDDS in children under the age of 5 years with suspected mitochondrial hepatopathy and to evaluate this group of patients using MDDS gene panel and clinical exome sequencing (CES) genetic analysis methods.
Methods: Patients under 5 years of age who were clinically suspected to have mitochondrial hepatopathy and had neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset were included.
Results: Forty patients (20 female, 50%) were enrolled, with a median age of 102 [57-263.8] days. Icteric appearance was identified in 28 (70%) of the patients, hepatomegaly in 27 (67.5%), splenomegaly in 10 (25.0%), and hypotonicity in 10 (25.0%); moreover, elevated international normalized ratio was detected in 77.5%, cholestasis in 77.5%, and elevated lactate levels in 62.5%. Molecular genetic diagnosis was made in 9 patients (22.5%) with the MDDS gene panel and in 17 (42.5%) patients with the CES analysis. All patients diagnosed with MDDS had a history of parental consanguinity, while the rate in those without MDDS was 54.8% (p = 0.012). High lactate levels were identified in all those with MDDS, but in only 51.6% of those without MDDS (p = 0.020).
Conclusion: Present study revealed that demographic findings and laboratory assessments are insufficient to diagnose genetically inherited diseases in children presenting with hepatic involvement. While one-fifth of the patients with suspected mitochondrial hepatopathies were diagnosed with MDDS, it is revealed that around half of patients can be diagnosed with CES panel.

Keywords:  Clinical exome sequencing analysis; Gene panel; Hepatopathy; Mitochondria; Mitochondrial DNA depletion syndrome

DOI:  https://doi.org/10.1159/000539034
ACS Synth Biol. 2024 Dec 04.

Toward a Quadruplet Codon Mitochondrial Genetic Code.

Michael L Pigula, Yahui Ban, Peter G Schultz.

  Nature has evolved to exclusively use a genetic code consisting of triplet nucleotide codons. The translation system, however, is known to be compatible with 4-nucleotide frameshift or quadruplet codons. In this study, we begin to explore the possibility of a genome made up entirely of quadruplet codons using the minimal mitochondrial genome of Saccharomyces cerevisiae as a model system. We demonstrate that mitochondrial tryptophanyl- and tyrosyl-tRNAs with modified anticodons effectively suppress mutant cox3 genes containing a TAG stop or TAGA quadruplet codon, leading to the production of full-length COX3 and a respiratory-competent phenotype. This work provides a method for introducing heterologous tRNAs into the yeast mitochondria for genetic engineering applications and serves as a starting point for the development of a quadruplet codon genetic code.

Keywords:  genome recoding; mitochondria; quadruplet codon; tRNA engineering

DOI:  https://doi.org/10.1021/acssynbio.4c00630
EBioMedicine. 2024 Nov 29. pii: S2352-3964(24)00512-7. [Epub ahead of print]110 105476

Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.

Chia-Yi Li, Li-Wen Chen, Meng-Che Tsai, Yen-Yin Chou, Pei-Xuan Lin, Yu-Ming Chang, Wuh-Liang Hwu, Yin-Hsiu Chien, Ju-Li Lin, Hui-An Chen, Ni-Chung Lee, Pen-Hua Su, Tzung-Chien Hsieh, Hannah Klinkhammer, Yi-Chieh Wang, Yi-Ting Huang, Peter M Krawitz, Sheng-Hsiang Lin, Lynn L H Huang, Po-Min Chiang, Min-Hsiu Shih, Peng-Chieh Chen.

   BACKGROUND: Impaired mitochondrial protein import machinery leads to phenotypically heterogeneous diseases. Here, we report a recurrent homozygous missense variant in the gene that encodes the translocase of outer mitochondrial membrane 7 (TOMM7) in nine patients with microcephaly, short stature, facial dysmorphia, atrophic macular scarring, and moyamoya disease from seven unrelated families.
METHODS: To prove the causality of the TOMM7 variant, mitochondrial morphology, proteomics, and respiration were investigated in CRISPR/Cas9-edited iPSCs-derived endothelial cells. Cerebrovascular defects and mitochondrial respiration were also examined in CRISPR/Cas9-edited zebrafish.
FINDINGS: iPSC-derived endothelial cells with homozygous TOMM7 p.P29L showed increased TOM7 stability, enlarged mitochondria, increased senescence, and defective tube formation. In addition, proteomic analysis revealed a reduced abundance of mitochondrial proteins involved in ATP synthesis or coordinating TCA cycle and gluconeogenesis. Moreover, mitochondrial respiration was slightly decreased while ATP production from glycolysis was significantly increased. Furthermore, deletion of tomm7 in zebrafish caused craniofacial and cerebrovascular defects that recapitulated human phenotypes. Notably, homozygous iPSCs differentially expressed genes involved in glycolysis and response to hypoxia. Finally, the metabolic imbalance was evidenced by decreased oxygen consumption, increased level of hexokinase 2, and enhanced glycolysis in endothelial cells derived from the patient's iPSCs.
INTERPRETATION: These results revealed the essential role of TOMM7 in balancing cellular sources of energy production at both proteomic and transcriptomic levels and provided the molecular mechanisms through which TOMM7 p.P29L variant leads to an autosomal recessive microcephalic osteodysplastic dwarfism with moyamoya disease.
FUNDING: This work is supported by National Science and Technology Council grants and National Cheng Kung University Hospital.

Keywords:  Cerebrovascular disease; Glycolysis; Mitochondrial protein import; Mitochondrial respiration; TOM complex; iPSC-derived endothelial cells

DOI:  https://doi.org/10.1016/j.ebiom.2024.105476
Redox Biol. 2024 Nov 29. pii: S2213-2317(24)00426-9. [Epub ahead of print] 103448

Mitochondrial metabolism and redox signaling.

Annika Müller-Eigner, Andrew P Wojtovich.

DOI: https://doi.org/10.1016/j.redox.2024.103448
J Pathol. 2024 Dec 03.

Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells.

Jaeeun Lee, Hayoung Woo, Hyunju Kang, Young-Ki Park, Ji-Young Lee.

  The pathogenesis of alcohol-related liver disease (ALD) is closely linked to mitochondrial dysfunction and impaired cellular energy metabolism. In this study, we explored how ethanol triggers inflammation, oxidative stress, and mitochondrial dysfunction in Kupffer cells, i.e.hepatic resident macrophages, primarily focusing on the mitochondrial unfolded protein response (UPRmt) using immortalized mouse Kupffer cells (ImKCs) and mouse primary KCs. The UPRmt is a cellular defense mechanism activated in response to the perturbation of mitochondrial proteostasis to maintain mitochondrial integrity and function by upregulating the expression of mitochondrial chaperones and proteases. We also determined whether nicotinamide riboside (NR), a NAD+ precursor, could mitigate ethanol-triggered cellular damage. When ImKCs were exposed to 80 mm ethanol for 72 h, they displayed inflammation, oxidative stress, and impaired mitochondrial function with decreased mitochondrial content and deformed mitochondrial crista structure. NR, however, counteracted the effects of ethanol. Furthermore, ethanol increased mRNA and protein levels of UPRmt genes, such as mitochondrial chaperones and proteases, which were attenuated by NR. Notably, the ethanol-induced shift in the entry of activating transcription factor 5 (ATF5), a putative transcriptional regulator of UPRmt, to the nucleus from the mitochondria was abolished by NR. The induction of UPRmt genes by ethanol was significantly repressed when Atf5 was knocked down, indicating the role of ATF5 in the induction of UPRmt genes in ImKCs exposed to ethanol. We also confirmed the induction of UPRmt gene expression in mouse and human livers exposed to alcohol. Our findings demonstrate the ability of NR to alleviate ethanol-induced oxidative stress, inflammation, and mitochondrial dysfunction, partly by modulating the ATF5-dependent UPRmt pathway in ImKCs, suggesting its potential for ALD therapy. © 2024 The Pathological Society of Great Britain and Ireland.

Keywords:  Kupffer cells; ethanol metabolism; mitochondrial unfolded protein response; nicotinamide riboside

DOI:  https://doi.org/10.1002/path.6372
Phys Chem Chem Phys. 2024 Dec 02.

Respiratory complex II acting as a homeostatic regulatory sensor.

Muhammad A Hagras.

The succinate-ubiquinone oxidoreductase (SQR) complex connects two of the cell's most vital energy-producing metabolic processes: the tricarboxylic acid cycle and the electron transport chain. Hence, the SQR complex is essential in cell metabolism, and its malfunction leads to the progression of multiple metabolic disorders and other diseases, such as cancer. In the current study, we calculated the electron tunneling (ET) pathways between the different redox systems in the SQR complex, including the SQR ligands and the distant heme b redox center, using the broken-symmetry semi-empirical ZINDO method. Interestingly, we discovered a water channel running from the mitochondrial matrix, filling the space between Fe3S4 and heme b redox centers. To investigate the physiological function of the water channel, we performed extensive molecular dynamics (MD) simulations of the membrane-embedded SQR complex in small and large water boxes, representing regular (MDA) and extended (MDB) volume states, respectively. We found that under regular volume conditions (MDA), the ET reaction is conducted through both the iron-sulfur cluster chain (i.e., pathway A) and through heme b (i.e., pathway B). Hence, the SQR complex encompasses an internal interferometer similar to the Mach-Zender interferometer, such that the tunneling electron experiences a self-interference effect through pathways A and B, enhancing the SQR complex's overall ET thermodynamics and favoring the forward ET direction of oxidizing succinate to fumarate and reducing ubiquinone to ubiquinol. On the other hand, we found that under extended volume conditions (MDB), the internal water channel of the SQR complex "senses" the expansion in the mitochondrial volume, pushing the heme b and Fe4S3 redox centers apart and hence lowering the SQR equilibrium constant to almost unity. Therefore, the SQR complex could be driven to work in the reverse direction, catalyzing the production of ubiquinone molecules essential for the physiological function of respiratory complexes I and III and restoring the inner-mitochondrial membrane potential, which leads to restoring the function of the H-K anti-porter, pumping K+ outward from the matrix and restoring the regular mitochondrial volume.

DOI: https://doi.org/10.1039/d4cp03552f
Hum Genomics. 2024 Dec 05. 18(1): 136

An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy.

Luis R Lopes, William L Macken, Seth Du Preez, Huafrin Kotwal, Konstantinos Savvatis, Neha Sekhri, Saidi A Mohiddin, Renata Kabiljo, Robert D S Pitceathly.

   BACKGROUND: A significant proportion of cardiomyopathy patients remain genetically unsolved. Our aim was to use the large genomes cohort of the 100,000 genomes project (100KGP) to explore the proportion of potentially causal mitochondrial (mtDNA) variants in cardiomyopathy patients, particularly in genotype-elusive participants. The homoplasmic MT-TI 4300A>G is unusual in that it typically presents with a cardiac-only phenotype, but MT-TI is currently not part of the genes analysed for non-syndromic cardiomyopathies.
RESULTS: We analysed 1363 cardiomyopathy genomes from the 100KGP project (of which only 172 had been previously solved) to detect disease causing mtDNA variants. MitoHPC was used to call variants. For controls, 1329 random subjects not recruited for a cardiomyopathy diagnosis and not related to any participant in the cardiomyopathy cohort were selected. We have additionally compared the frequency of detected variants with published UK Biobank data. Pathogenicity annotations were assigned based on MitoMap. Four patients, all with a diagnosis of hypertrophic cardiomyopathy (HCM) and without a previously identified genetic cause from the 100KGP clinical-standard analysis, were found to harbour the pathogenic MT-TI m.4300A>G variant (0.6% of HCM cases without a diagnosis).
CONCLUSION: These data support the inclusion of MT-TI in the initial genetic testing panel for (non-syndromic) HCM.

Keywords:  Hypertrophic cardiomyopathy; Mitochondrial DNA; Whole Genome Sequencing; m.4300A>G

DOI:  https://doi.org/10.1186/s40246-024-00702-9
Neurosci Biobehav Rev. 2024 Dec 03. pii: S0149-7634(24)00440-8. [Epub ahead of print] 105971

Mitochondrial Transplantation in Brain Disorders: Achievements, Methods, and Challenges.

Aurélien Riou, Aline Broeglin, Amandine Grimm.

  Mitochondrial transplantation is a new treatment strategy aimed at repairing cellular damage by introducing healthy mitochondria into injured cells. The approach shows promise in protecting brain function in various neurological disorders such as traumatic brain injury/ischemia, neurodegenerative diseases, cognitive disorders, and cancer. These conditions are often characterized by mitochondrial dysfunction, leading to impaired energy production and neuronal death. The review highlights promising preclinical studies where mitochondrial transplantation has been shown to restore mitochondrial function, reduce inflammation, and improve cognitive and motor functions in several animal models. It also addresses significant challenges that must be overcome before this therapy can be clinically applied. Current efforts to overcome these challenges, including advancements in isolation techniques, cryopreservation methods, finding an appropriate mitochondria source, and potential delivery routes, are discussed. Considering the rising incidence of neurological disorders and the limited effectiveness of current treatments, this review offers a comprehensive overview of the current state of mitochondrial transplantation research and critically assesses the remaining obstacles. It provides valuable insights that could steer future studies and potentially lead to more effective treatments for various brain disorders.

Keywords:  Cognitive disorders; ischemia; mitochondrial transplantation; neurodegenerative diseases; traumatic brain injury

DOI:  https://doi.org/10.1016/j.neubiorev.2024.105971
J Clin Invest. 2024 Dec 02. pii: e185569. [Epub ahead of print]134(23):

Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α.

Hong Wang, Maria Miranda, Eizo Marutani, Paul Lichtenegger, Gregory R Wojtkiewicz, Fumito Ichinose, Vamsi K Mootha.



Keywords:  Genetics; Hypoxia

DOI:  https://doi.org/10.1172/JCI185569
Cell Death Dis. 2024 Dec 05. 15(12): 881

SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia.

Alice Zhao, Laura Maple, Juwei Jiang, Katie N Myers, Callum G Jones, Hannah Gagg, Connor McGarrity-Cottrell, Ola Rominiyi, Spencer J Collis, Greg Wells, Marufur Rahman, Sarah J Danson, Darren Robinson, Carl Smythe, Chun Guo.

SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia. Furthermore, we identify deSUMO2/3-ylation enzyme SENP3 and mitochondrial Fission protein 1 (FIS1) as key players in hypoxia-induced mitophagy (HIM), with SUMOylatable FIS1 acting as a crucial regulator for SENP3-mediated HIM regulation. Interestingly, we find that hypoxia promotes FIS1 SUMO2/3-ylation and triggers an interaction between SUMOylatable FIS1 and Rab GTPase-activating protein Tre-2/Bub2/Cdc16 domain 1 family member 17 (TBC1D17), which in turn suppresses HIM. Therefore, we propose a novel SUMOylation-dependent pathway where the SENP3-FIS1 axis promotes HIM, with TBC1D17 acting as a fine-tuning regulator. Importantly, the SENP3-FIS1 axis plays a protective role against hypoxia-induced cell death, highlighting its physiological significance, and hypoxia-inducible FIS1-TBC1D17 interaction is detectable in primary glioma stem cell-like (GSC) cultures derived from glioblastoma patients, suggesting its disease relevance. Our findings not only provide new insights into SUMOylation/deSUMOylation regulation of HIM but also suggest the potential of targeting this pathway to enhance cellular resilience under hypoxic stress.

DOI: https://doi.org/10.1038/s41419-024-07271-8
Mol Genet Genomic Med. 2024 Dec;12(12): e70037

Homozygous Microdeletion Involving Exon 1 of ERCC8 and NDUFAF2 With Uniparental Isodisomy of Chromosome 5.

Kaori Yamoto, Kosuke Yamada, Kenji Shimizu, Sachiko Miyamoto, Mitsuko Nakashima, Hirotomo Saitsu.

   BACKGROUND: Uniparental isodisomy (UPiD) refers to a condition, in which both homologous chromosomes are inherited from only one parental homolog, which can result in either imprinting disorders or autosomal recessive conditions.
METHODS: We performed chromosomal microarray analysis, exome sequencing (ES), and RNA sequencing (RNA-seq) using the patient's urine-derived cells on a patient with growth retardation and multiple congenital anomalies.
RESULTS: We identified a homozygous ~0.53 kb microdeletion at 5q12.1, which was transmitted from the father with paternal UPiD(5). The deletion encompassed the first exon of both the ERCC8 and NDUFAF2 genes, which are responsible for Cockayne syndrome (CS) and mitochondrial complex I deficiency, respectively. Furthermore, RNA-seq confirmed the reduced expression of both genes. Indeed, in addition to clinical features common to both syndromes, such as growth retardation, developmental delay, and feeding difficulties, the patient exhibited blended phenotypes: the characteristic features of CS, including arthrogryposis, microcephaly, and facial dysmorphisms, and those of mitochondrial complex I deficiency, including high serum lactate levels and lethal apnea resulting in a severe clinical course.
CONCLUSION: The results imply that ES in combination with RNA-seq could be a powerful method for the detection of underlying factors responsible for rare genetic conditions, such as UPD.

Keywords:   ERCC8 ; NDUFAF2 ; RNA sequencing; homozygous deletion; uniparental disomy

DOI:  https://doi.org/10.1002/mgg3.70037
Sci Rep. 2024 12 04. 14(1): 30206

Identification of rare disease genes as drivers of common diseases through tissue-specific gene regulatory networks.

Olivier B Bakker, Annique Claringbould, Harm-Jan Westra, Henry Wiersma, Floranne Boulogne, Urmo Võsa, Carlos G Urzúa-Traslaviña, Sophie Mulcahy Symmons, Mahmoud M M Zidan, Marie C Sadler, Zoltán Kutalik, Iris H Jonkers, Lude Franke, Patrick Deelen.

Genetic variants identified through genome-wide association studies (GWAS) are typically non-coding, exerting small regulatory effects on downstream genes. However, which downstream genes are ultimately impacted and how they confer risk remains mostly unclear. By contrast, variants that cause rare Mendelian diseases are often coding and have a more direct impact on disease development. Here we demonstrate that common and rare genetic diseases can be linked by studying how common disease-associated variants influence gene co-expression in 57 different tissues and cell types. We implemented this method in a framework called Downstreamer and applied it to 88 GWAS traits. We find that predicted downstream "genes" are enriched with Mendelian disease genes, e.g. key genes for height are enriched for genes that cause skeletal abnormalities and Ehlers-Danlos syndromes. 78% of these key genes are located outside of GWAS loci, suggesting that they result from complex trans regulation rather than being impacted by disease-associated variants in cis. Based on our findings, we discuss the challenges in reconstructing gene regulatory networks and provide a roadmap to improve the identification of these highly connected genes linked to common traits and diseases.

DOI: https://doi.org/10.1038/s41598-024-80670-1
Elife. 2024 Dec 03. pii: e88231. [Epub ahead of print]13

Understanding genetic variants in context.

Nasa Sinnott-Armstrong, Stanley Fields, Frederick Roth, Lea M Starita, Cole Trapnell, Judit Villen, Douglas M Fowler, Christine Queitsch.

  Over the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes - most notably functional regulatory elements - in the development and progression of these diseases. Simultaneously, scientists have increasingly used multiplex assays of variant effect to systematically phenotype the cellular consequences of millions of genetic variants. In this article, we argue that the context of genetic variants - at all scales, from other genetic variants and gene regulation to cell biology to organismal environment - are critical components of how we can employ genomics to interpret these variants, and ultimately treat these diseases. We describe approaches to extend existing experimental assays and computational approaches to examine and quantify the importance of this context, including through causal analytic approaches. Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge.

Keywords:  epistasis; genetics; gene–environment interactions; genomics; multiplexed assays of variant effect

DOI:  https://doi.org/10.7554/eLife.88231
Nat Commun. 2024 Dec 04. 15(1): 10582

Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation.

Yating Liu, Qian Li, Guojing Tian, Xinyi Zhou, Panpan Chen, Bo Chen, Zhao Shan, Bin Qi.

All organisms depend on food digestion for survival, yet the brain-gut signaling mechanisms that regulate this process are not fully understood. Here, using an established C. elegans digestion model, we uncover a pathway in which neuronal ROS (free radicals) signal the intestine to suppress digestion. Genetic screening reveals that reducing genes responsible for maintaining ROS balance increases free radicals and decreases digestion. PRDX-2 knockout in olfactory neurons (AWC) elevates ROS and reduces digestive capacity, mediated by the neuropeptide NLP-1 and activation of the mitochondrial unfolded protein response (UPRmt) in the intestine. Additionally, over-expressing nlp-1 or ablating AWC neurons both trigger UPRmt and inhibit digestion. These findings reveal a brain-gut connection in which neuronal PRDX-2-mediated ROS signaling modulates food digestion, highlighting a critical role of free radicals in shutting down digestion to alleviate stress and reduce food consumption.

DOI: https://doi.org/10.1038/s41467-024-55013-3
Sci Rep. 2024 12 03. 14(1): 30144

A fully automated morphological analysis of yeast mitochondria from wide-field fluorescence images.

Jana Vojtová, Martin Čapek, Sabrina Willeit, Tomáš Groušl, Věra Chvalová, Eva Kutejová, Vladimír Pevala, Leoš Shivaya Valášek, Mark Rinnerthaler.

  Mitochondrial morphology is an important parameter of cellular fitness. Although many approaches are available for assessing mitochondrial morphology in mammalian cells, only a few technically demanding and laborious methods are available for yeast cells. A robust, fully automated and user-friendly approach that would allow (1) segmentation of tubular and spherical mitochondria in the yeast Saccharomyces cerevisiae from conventional wide-field fluorescence images and (2) quantitative assessment of mitochondrial morphology is lacking. To address this, we compared Global thresholding segmentation with deep learning MitoSegNet segmentation, which we retrained on yeast cells. The deep learning model outperformed the Global thresholding segmentation. We applied it to segment mitochondria in strain lacking the MMI1/TMA19 gene encoding an ortholog of the human TCTP protein. Next, we performed a quantitative evaluation of segmented mitochondria by analyses available in ImageJ/Fiji and by MitoA analysis available in the MitoSegNet toolbox. By monitoring a wide range of morphological parameters, we described a novel mitochondrial phenotype of the mmi1Δ strain after its exposure to oxidative stress compared to that of the wild-type strain. The retrained deep learning model, all macros applied to run the analyses, as well as the detailed procedure are now available at https://github.com/LMCF-IMG/Morphology_Yeast_Mitochondria .

Keywords:  Deep learning; Mitochondria; Mmi1; Oxidative stress; TCTP; Yeast

DOI:  https://doi.org/10.1038/s41598-024-81241-0
EMBO Rep. 2024 Dec 02.

Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.

Magdalena Shumanska, Dmitri Lodygin, Christine S Gibhardt, Christian Ickes, Ioana Stejerean-Todoran, Lena C M Krause, Kira Pahl, Lianne J H C Jacobs, Andrea Paluschkiwitz, Shuya Liu, Angela Boshnakovska, Niels Voigt, Tobias J Legler, Martin Haubrock, Miso Mitkovski, Gereon Poschmann, Peter Rehling, Sven Dennerlein, Jan Riemer, Alexander Flügel, Ivan Bogeski.

  T-cell receptor (TCR)-induced Ca2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca2+-uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca2+ (mCa2+) uptake in primary naive and effector human CD4+ T-cells. Compared to naive T-cells, effector T-cells display elevated mCa2+ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUaKD), diminishes mCa2+ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUaKD in rat CD4+ T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that mCa2+ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.

Keywords:  Autoimmunity; Calcium; MCU; Mitochondria; T-cell

DOI:  https://doi.org/10.1038/s44319-024-00313-4
Br J Biomed Sci. 2024 ;81 13707

Pioneering Advances and Innovative Applications of Mesoporous Carriers for Mitochondria-Targeted Therapeutics.

Mohamad Anas Al Tahan, Sana Al Tahan.

  Mitochondria, known as the cell's powerhouse, play a critical role in energy production, cellular maintenance, and stemness regulation in non-cancerous cells. Despite their importance, using drug delivery systems to target the mitochondria presents significant challenges due to several barriers, including cellular uptake limitations, enzymatic degradation, and the mitochondrial membranes themselves. Additionally, barriers in the organs to be targetted, along with extracellular barriers formed by physiological processes such as the reticuloendothelial system, contribute to the rapid elimination of nanoparticles designed for mitochondrial-based drug delivery. Overcoming these challenges has led to the development of various strategies, such as molecular targeting using cell-penetrating peptides, genomic editing, and nanoparticle-based systems, including porous carriers, liposomes, micelles, and Mito-Porters. Porous carriers stand out as particularly promising candidates as drug delivery systems for targeting the mitochondria due to their large pore size, surface area, and ease of functionalisation. Depending on the pore size, they can be classified as micro-, meso-, or macroporous and are either ordered or non-ordered based on both size and pore uniformity. Several methods are employed to target the mitochondria using porous carriers, such as surface modifications with polyethylene glycol (PEG), incorporation of targeting ligands like triphenylphosphonium, and capping the pores with gold nanoparticles or chitosan to enable controlled and triggered drug delivery. Photodynamic therapy is another approach, where drug-loaded porous carriers generate reactive oxygen species (ROS) to enhance mitochondrial targeting. Further advancements have been made in the form of functionalised porous silica and carbon nanoparticles, which have demonstrated potential for effective drug delivery to mitochondria. This review highlights the various approaches that utilise porous carriers, specifically focusing on silica-based systems, as efficient vehicles for targeting mitochondria, paving the way for improved drug delivery strategies in mitochondrial therapies.

Keywords:  TPP+; mesoporous silica; mitochondria; porous carriers; targeting

DOI:  https://doi.org/10.3389/bjbs.2024.13707
J Drug Target. 2024 Dec 02. 1-22

Mitochondrial-targeted liposome-based drug delivery - Therapeutic potential and challenges.

Lissette Sanchez-Aranguren, Mohamad Anas Al Tahan, Muhammad Uppal, Parag Juvale, Mandeep Kaur Marwah.

  Liposomes, as nanocarriers for therapeutics, are a prominent focus in translational medicine. Given their biocompatibility, liposomes are suitable drug delivery systems rendering highly efficient therapeutic outcomes with minimal off-site toxicity. In different scenarios of human disease, it is essential not only to maintain therapeutic drug levels but also to target them to the appropriate intracellular compartment. Mitochondria regulate cellular signalling, calcium balance, and energy production, playing a crucial role in various human diseases. The notion of focusing on mitochondria for targeted drug delivery was proposed several decades ago, yet the practical application of this idea and its translation to clinical use is still in development. Mitochondrial-targeted liposomes offer an alternative to standard drug delivery systems, potentially reducing off-target interactions, side effects, and drug dosage or frequency. . To advance this field, it is imperative to integrate various disciplines such as efficient chemical design, pharmacology, pharmaceutics, and cell biology. This review summarises scientific advances in the design, development and characterisation of novel liposome-based drug delivery systems targeting the mitochondria while revisiting their translational potential.

Keywords:  liposomes; mitochondria; mitochondrial dysfunction; nanocarriers; targeted drug delivery

DOI:  https://doi.org/10.1080/1061186X.2024.2437440
Nat Prod Rep. 2024 Dec 02.

Effective data visualization strategies in untargeted metabolomics.

Kevin Mildau, Henry Ehlers, Mara Meisenburg, Elena Del Pup, Robert A Koetsier, Laura Rosina Torres Ortega, Niek F de Jonge, Kumar Saurabh Singh, Dora Ferreira, Kgalaletso Othibeng, Fidele Tugizimana, Florian Huber, Justin J J van der Hooft.

Covering: 2014 to 2023 for metabolomics, 2002 to 2023 for information visualizationLC-MS/MS-based untargeted metabolomics is a rapidly developing research field spawning increasing numbers of computational metabolomics tools assisting researchers with their complex data processing, analysis, and interpretation tasks. In this article, we review the entire untargeted metabolomics workflow from the perspective of information visualization, visual analytics and visual data integration. Data visualization is a crucial step at every stage of the metabolomics workflow, where it provides core components of data inspection, evaluation, and sharing capabilities. However, due to the large number of available data analysis tools and corresponding visualization components, it is hard for both users and developers to get an overview of what is already available and which tools are suitable for their analysis. In addition, there is little cross-pollination between the fields of data visualization and metabolomics, leaving visual tools to be designed in a secondary and mostly ad hoc fashion. With this review, we aim to bridge the gap between the fields of untargeted metabolomics and data visualization. First, we introduce data visualization to the untargeted metabolomics field as a topic worthy of its own dedicated research, and provide a primer on cutting-edge visualization research into data visualization for both researchers as well as developers active in metabolomics. We extend this primer with a discussion of best practices for data visualization as they have emerged from data visualization studies. Second, we provide a practical roadmap to the visual tool landscape and its use within the untargeted metabolomics field. Here, for several computational analysis stages within the untargeted metabolomics workflow, we provide an overview of commonly used visual strategies with practical examples. In this context, we will also outline promising areas for further research and development. We end the review with a set of recommendations for developers and users on how to make the best use of visualizations for more effective and transparent communication of results.

DOI: https://doi.org/10.1039/d4np00039k
Mol Syndromol. 2024 Dec;15(6): 481-486

A Novel NDUFV2 Variant in an Asymptomatic Adolescent Girl with Progressive Cavitating Leukoencephalopathy.

Emine Caliskan, Safiye Gunes Sager, Akif Ayaz, Kerem Teralı, Hediye Pinar Gunbey.

   Introduction: Pathogenic variants in several genes encoding components of the mitochondrial respiratory chain have been linked to various clinical phenotypes such as progressive cavitating leukoencephalopathy (PCL). The association between PCL, previously linked to numerous gene mutations in the literature, and the NDUFV2 gene mutations has emerged as a recent and noteworthy discovery. PCL is generally diagnosed in symptomatic patients during the early years of life, mostly in infancy.
Case Presentation: In a previously healthy 12-year-old Turkish girl, a computed tomography scan taken for minor head trauma incidentally revealed suspicious hypodense areas in the periventricular white matter. Subsequently, a magnetic resonance imaging evaluation was performed. There was no history of motor regression, irritability, or seizures up to the age of 12. The case exhibited normal neurological and cranial nerve examinations. Magnetic resonance imaging detected bilateral periventricular T2/FLAIR hyperintensities with cystic areas suggestive of PCL. Whole-exome sequencing revealed the presence of a homozygous p.R222C missense variant in the NDUFV2 gene. Over a 6-year follow-up period, the patient remained asymptomatic, and there were no discernible changes in the magnetic resonance imaging findings.
Conclusion: This case underscores the association between a potentially causal variant at the NDUFV2 locus and PCL. It is worth noting that this novel variation in PCL can not only manifest with symptoms in the infantile period but also remain asymptomatic into adolescence.

Keywords:  Diffusion-tensor imaging; Magnetic resonance imaging perfusion; Magnetic resonance imaging spectroscopy; NDUFV2; Progressive cavitating leukoencephalopathy

DOI:  https://doi.org/10.1159/000538900
Hepatol Commun. 2024 Dec 01. pii: e0598. [Epub ahead of print]8(12):

Missense variants in the TRPMr7 α-kinase domain are associated with recurrent pediatric acute liver failure.

Lea D Schlieben, Melanie T Achleitner, Billy Bourke, Max Diesner, René G Feichtinger, Alexander Fichtner, Christa Flechtenmacher, Nedim Hadzic, Robert Hegarty, Andreas Heilos, Andreas Janecke, Vassiliki Konstantopoulou, Dominic Lenz, Johannes A Mayr, Thomas Müller, Holger Prokisch, Georg F Vogel.

BACKGROUND: Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints.
METHODS: We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7).
RESULTS: We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF.
CONCLUSIONS: Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure.

DOI: https://doi.org/10.1097/HC9.0000000000000598