bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒01‒09
eighteen papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico

  1. Mitochondrion. 2022 Jan 03. pii: S1567-7249(21)00181-1. [Epub ahead of print]
      Mitochondrial dysfunction has been defined as a reduced efficiency of mitochondria to produce ATP given by a loss of mitochondrial membrane potential, alterations in the electron transport chain (ETC) function, with increase in reactive oxygen species (ROS) generation and decrease in oxygen consumption. During the last decades, mitochondrial dysfunction has been the focus of many researchers as a convergent point for the pathophysiology of several diseases. Numerous investigations have demonstrated that mitochondrial dysfunction is detrimental to cells, tissues and organisms, nevertheless, dysfunctional mitochondria can signal in a particular way in response to stress, a characteristic that may be useful to search for new therapeutic strategies with a common feature. The aim of this review addresses mitochondrial dysfunction and stress signaling as a promising target for future drug development.
    Keywords:  aged-associated diseases; mitochondrial UPR; mitochondrial dysfunction; mitochondrial morphology; mitophagy
  2. Dev Med Child Neurol. 2022 Jan 05.
    Childhood Basal Ganglia Disease Group
      AIM: To correlate clinical, radiological, and biochemical features with genetic findings in children with bilateral basal ganglia lesions of unknown aetiology, and propose a diagnostic algorithm for early recognition.METHOD: Children with basal ganglia disease were recruited in a 2-year prospective multicentre study for clinical, biomarker, and genetic studies. Radiological pattern recognition was examined by hierarchical clustering analysis.
    RESULTS: We identified 22 genetic conditions in 30 out of 62 paediatric patients (37 males, 25 females; mean age at onset 2y, SD 3; range 0-10y; mean age at assessment 11y, range 1-25y) through gene panels (n=11), whole-exome sequencing (n=13), and mitochondrial DNA (mtDNA) sequencing (n=6). Genetic aetiologies included mitochondrial diseases (57%), Aicardi-Goutières syndrome (20%), and monogenic causes of dystonia and/or epilepsy (17%) mimicking Leigh syndrome. Radiological abnormalities included T2-hyperintense lesions (n=26) and lesions caused by calcium or manganese mineralization (n=9). Three clusters were identified: the pallidal, neostriatal, and striatal, plus the last including mtDNA defects in the oxidative phosphorylation system with prominent brain atrophy. Mitochondrial biomarkers showed poor sensitivity and specificity in children with mitochondrial disease, whereas interferon signature was observed in all patients with patients with Aicardi-Goutières syndrome.
    INTERPRETATION: Combined whole-exome and mtDNA sequencing allowed the identification of several genetic conditions affecting basal ganglia metabolism. We propose a diagnostic algorithm which prioritizes early use of next-generation sequencing on the basis of three clusters of basal ganglia lesions.
  3. Front Genet. 2021 ;12 749792
      Neurodegenerative diseases (NDDs) are challenging to understand, diagnose, and treat. Revealing the genomic and transcriptomic changes in NDDs contributes greatly to the understanding of the diseases, their causes, and development. Moreover, it enables more precise genetic diagnosis and novel drug target identification that could potentially treat the diseases or at least ease the symptoms. In this study, we analyzed the transcriptional changes of nuclear-encoded mitochondrial (NEM) genes in eight NDDs to specifically address the association of these genes with the diseases. Previous studies show strong links between defects in NEM genes and neurodegeneration, yet connecting specific genes with NDDs is not well studied. Friedreich's ataxia (FRDA) is an NDD that cannot be treated effectively; therefore, we focused first on FRDA and compared the outcome with seven other NDDs, including Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Huntington's disease, multiple sclerosis, and Parkinson's disease. First, weighted correlation network analysis was performed on an FRDA RNA-Seq data set, focusing only on NEM genes. We then carried out differential gene expression analysis and pathway enrichment analysis to pinpoint differentially expressed genes that are potentially associated with one or more of the analyzed NDDs. Our findings propose a strong link between NEM genes and NDDs and suggest that our identified candidate genes can be potentially used as diagnostic markers and therapeutic targets.
    Keywords:  Parkinson’s disease (PD); alzheimers disease (AD); amytrophic lateral sclerosis (ALS); creutzfeld-jakob disease; friedreich ataxia (FRDA); frontotemporal dementia (FTD); huntington’s disease (HD); multiple sclerosis
  4. Mol Omics. 2022 Jan 04.
      MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical heterogeneity and the obscure genotype-phenotype correlation among MELAS patients. To gain insights into the pathogenic signature of MELAS, we designed a comprehensive strategy integrating proteomics and metabolomics in patient-derived dermal fibroblasts harboring the ultra-rare MELAS pathogenic variant m.14453G>A, specifically affecting the mitochondrial respiratory complex I. Global proteomics was achieved by data-dependent acquisition (DDA) and verified by data-independent acquisition (DIA) using both Spectronaut and the recently launched MaxDIA platforms. Comprehensive metabolite coverage was achieved for both polar and nonpolar metabolites in both reverse phase and HILIC LC-MS/MS analyses. Our proof-of-principle MELAS study with multi-omics integration revealed OXPHOS dysregulation with a predominant deficiency of complex I subunits, as well as alterations in key bioenergetic pathways, glycolysis, tricarboxylic acid cycle, and fatty acid β-oxidation. The most clinically relevant discovery is the downregulation of the arginine biosynthesis pathway, likely due to blocked argininosuccinate synthase, which is congruent with the MELAS cardinal symptom of stroke-like episodes and its current treatment by arginine infusion. In conclusion, we demonstrated an integrated proteomic and metabolomic strategy for patient-derived fibroblasts, which has great clinical potential to discover therapeutic targets and design personalized interventions after validation with a larger patient cohort in the future.
  5. Neurocase. 2022 Jan 04. 1-3
      Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited disorders characterised by cerebral iron overload mainly in the basal ganglia. Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a form of NBIA caused by pathogenic C19orf12 gene variants. We report on a Romanian patient with MPAN confirmed through exome sequencing, revealing a homozygous nonsense variant in the C19orf12 gene, NM_001031726.3: c.215T>G (p.Leu72*), that co-segregates with disease in tested relatives: the patient`s parents, younger brother and paternal uncle are heterozygous carriers. This is a novel disease-causing variant in the C19orf12 gene and the first reported MPAN case in a Romanian patient.
    Keywords:  C19orf12; mitochondrial membrane protein-associated neurodegeneration; neurodegeneration with brain iron accumulation
  6. J Child Neurol. 2022 Jan 05. 8830738211067065
      BACKGROUND: POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population.METHODS: Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia.
    RESULTS: A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain.
    CONCLUSIONS: We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.
    Keywords:  Alpers; Leigh; mitochondrial disease; mtDNA depletion; ophthalmoplegia
  7. iScience. 2021 Dec 17. 24(12): 103484
      Brain development is a highly orchestrated process requiring spatiotemporally regulated mitochondrial dynamics. Drp1, a key molecule in the mitochondrial fission machinery, undergoes various post-translational modifications including conjugation to the small ubiquitin-like modifier (SUMO). However, the functional significance of SUMOylation/deSUMOylation on Drp1 remains controversial. SUMO-specific protease 5 (Senp5L) catalyzes the deSUMOylation of Drp1. We revealed that a splicing variant of Senp5L, Senp5S, which lacks peptidase activity, prevents deSUMOylation of Drp1 by competing against other Senps. The altered SUMOylation level of Drp1 induced by Senp5L/5S affects mitochondrial morphology probably through controlling Drp1 ubiquitination and tubulation of the endoplasmic reticulum. A dynamic SUMOylation/deSUMOylation balance controls neuronal polarization and migration during the development of the cerebral cortex. These findings suggest a novel role of post-translational modification, in which deSUMOylation enzyme isoforms competitively regulate mitochondrial dynamics via Drp1 SUMOylation levels, in a tightly controlled process of neuronal differentiation and corticogenesis.
    Keywords:  Cellular neuroscience; Molecular neuroscience; Molecular physiology
  8. Front Cell Dev Biol. 2021 ;9 795838
      The regulatory role of actin cytoskeleton on mitochondrial function is a growing research field, but the underlying molecular mechanisms remain poorly understood. Specific actin-binding proteins (ABPs), such as Gelsolin, have also been shown to participate in the pathophysiology of mitochondrial OXPHOS disorders through yet to be defined mechanisms. In this mini-review, we will summarize the experimental evidence supporting the fundamental roles of actin cytoskeleton and ABPs on mitochondrial trafficking, dynamics, biogenesis, metabolism and apoptosis, with a particular focus on Gelsolin involvement in mitochondrial disorders. The functional interplay between the actin cytoskeleton, ABPs and mitochondrial membranes for the regulation of cellular homeostasis thus emerges as a new exciting field for future research and therapeutic approaches.
    Keywords:  OXPHOS system; actin cytoskeleton; gelsolin; mitochondria; mitochondrial disease
  9. EMBO Rep. 2022 Jan 07. e48754
      Mitochondria are unavoidably subject to organellar stress resulting from exposure to a range of reactive molecular species. Consequently, cells operate a poorly understood quality control programme of mitophagy to facilitate elimination of dysfunctional mitochondria. Here, we used a model stressor, deferiprone (DFP), to investigate the molecular basis for stress-induced mitophagy. We show that mitochondrial fission 1 protein (Fis1) is required for DFP-induced mitophagy and that Fis1 is SUMOylated at K149, an amino acid residue critical for Fis1 mitochondrial localization. We find that DFP treatment leads to the stabilization of the SUMO protease SENP3, which is mediated by downregulation of the E3 ubiquitin (Ub) ligase CHIP. SENP3 is responsible for Fis1 deSUMOylation and depletion of SENP3 abolishes DFP-induced mitophagy. Furthermore, preventing Fis1 SUMOylation by conservative K149R mutation enhances Fis1 mitochondrial localization. Critically, expressing a Fis1 K149R mutant restores DFP-induced mitophagy in SENP3-depleted cells. Thus, we propose a model in which SENP3-mediated deSUMOylation facilitates Fis1 mitochondrial localization to underpin stress-induced mitophagy.
    Keywords:  Fis1; SENP3; SUMO; mitophagy; organellar stress
  10. Autophagy. 2022 Jan 05. 1-16
      Barth syndrome (BTHS) is an X-linked genetic disorder caused by mutations in the TAFAZZIN/Taz gene which encodes a transacylase required for cardiolipin remodeling. Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining mitochondrial membrane structure, respiration, mtDNA biogenesis, and mitophagy. Mutations in the TAFAZZIN gene deplete mature cardiolipin, leading to mitochondrial dysfunction, dilated cardiomyopathy, and premature death in BTHS patients. Currently, there is no effective treatment for this debilitating condition. In this study, we showed that TAFAZZIN deficiency caused hyperactivation of MTORC1 signaling and defective mitophagy, leading to accumulation of autophagic vacuoles and dysfunctional mitochondria in the heart of Tafazzin knockdown mice, a rodent model of BTHS. Consequently, treatment of TAFAZZIN knockdown mice with rapamycin, a potent inhibitor of MTORC1, not only restored mitophagy, but also mitigated mitochondrial dysfunction and dilated cardiomyopathy. Taken together, these findings identify MTORC1 as a novel therapeutic target for BTHS, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for BTHS.Abbreviations: BTHS: Barth syndrome; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CL: cardiolipin; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; KD: knockdown; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LV: left ventricle; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; OCR: oxygen consumption rate; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; qRT-PCR: quantitative real-time polymerase chain reaction; RPS6KB/S6K: ribosomal protein S6 kinase beta; SQSTM1/p62: sequestosome 1; TLCL: tetralinoleoyl cardiolipin; WT: wild-type.
    Keywords:  BTHS; MTORC1; TAFAZZIN; cardiolipin; mitophagy; rapamycin
  11. Neurol India. 2021 Nov-Dec;69(6):69(6): 1817-1819
      Mitochondrial DNA depletion syndromes (MDS) are rare mitochondrial disorders with evolving broad genotype and phenotype. This is a first case report from India about MPV 17, a mitochondrial inner membrane protein gene variant mutation, presenting with neuropathy, leucoencephalopathy and subclinical hepatic dysfunction with detailed clinical and imaging description.
    Keywords:  MPV17 gene; Mitochondrial depletion syndromes; neuropathy and leukoencephalopathy
  12. FEBS J. 2022 Jan 05.
      Nek4 is a serine/threonine kinase which has been implicated in primary cilia stabilization, DNA damage response, autophagy and epithelial-to-mesenchymal transition. The role of Nek4 in cancer cell survival and chemotherapy resistance has also been shown. However, the precise mechanisms by which Nek4 operates remain to be elucidated. Here, we show that Nek4 overexpression activates mitochondrial respiration coupled to ATP production, which is paralleled by increased mitochondrial membrane potential, and resistance to mitochondrial DNA damage. Congruently, Nek4 depletion reduced mitochondrial respiration and mtDNA integrity. Nek4 deficiency caused mitochondrial elongation, probably via reduced activity of the fission protein DRP1. In Nek4 overexpressing cells the increase in mitochondrial fission was concomitant to enhanced phosphorylation of DRP1 and Erk1/2 proteins, and the effects on mitochondrial respiration were abolished in the presence of a DRP1 inhibitor. This study shows Nek4 as a novel regulator of mitochondrial function that may explain the joint appearance of high mitochondrial respiration and mitochondrial fragmentation.
    Keywords:  DRP1; Nek4; fission; mitochondrial function
  13. Mol Genet Metab. 2021 Dec 08. pii: S1096-7192(21)01174-4. [Epub ahead of print]
      Several studies have shown serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels are elevated in patients with mitochondrial disease (MD) where myopathy is a feature. In this study we investigated the utility of FGF21 and GDF15 as biomarkers for MD in a phenotypically and genotypically diverse pediatric cohort with suspected MD against a panel of healthy controls and non-mitochondrial disease controls with some overlapping clinical features. Serum was collected from 56 children with MD, 104 children with non-mitochondrial disease (27 neuromuscular, 26 cardiac, 21 hepatic, 30 renal) and 30 pediatric controls. Serum FGF21 and GDF15 concentrations were measured using ELISA, and their ability to detect MD was determined. Median FGF21 and GDF15 serum concentrations were elevated 17-fold and 3-fold respectively in pediatric MD patients compared to the healthy control group. Non-mitochondrial disease controls had elevated serum GDF15 concentrations while FGF21 concentrations were in the normal range. Elevation of GDF15 in a range of non-mitochondrial pediatric disorders limits its use as a MD biomarker. FGF21 was elevated in MD patients with a spectrum of clinical phenotypes, including those without myopathy. Serum FGF21 had an area under the receiver operating characteristic curve of 0.87, indicating good ability to discriminate between pediatric MD and healthy and non-mitochondrial disease controls. Triaging of pediatric MD patients by clinical phenotyping and serum FGF21 testing, followed by massively parallel sequencing, may enable more rapid diagnosis of pediatric MD.
    Keywords:  Biomarker; Diagnosis; FGF21; GDF15; Mitochondrial disease; Pediatric
  14. Cell Regen. 2022 Jan 04. 11(1): 1
      Studying the etiology of human neurodevelopmental diseases has long been a challenging task due to the brain's complexity and its limited accessibility. Human pluripotent stem cells (hPSCs)-derived brain organoids are capable of recapitulating various features and functionalities of the human brain, allowing the investigation of intricate pathogenesis of developmental abnormalities. Over the past years, brain organoids have facilitated identifying disease-associated phenotypes and underlying mechanisms for human neurodevelopmental diseases. Integrating with more cutting-edge technologies, particularly gene editing, brain organoids further empower human disease modeling. Here, we review the latest progress in modeling human neurodevelopmental disorders with brain organoids.
    Keywords:  Brain organoids; Disease modeling; Gene editing; Neurodevepmental diseases; Stem cells
  15. Methods Mol Biol. 2022 ;2378 249-259
      The nematode Caenorhabditis elegans is a powerful model to study cellular stress responses. Due to its transparency and ease of genetic manipulation, C. elegans is especially suitable for fluorescence microscopy. As a result, studies of C. elegans using different fluorescent reporters have led to the discovery of key players of cellular stress response pathways, including the mitochondrial unfolded protein response (UPRmt). UPRmt is a protective retrograde signaling pathway that ensures mitochondrial homeostasis. The nuclear genes hsp-6 and hsp-60 encode mitochondrial chaperones and are highly expressed upon UPRmt induction. The transcriptional reporters of these genes, hsp-6::gfp and hsp-60::gfp, have been instrumental for monitoring this pathway in live animals. Additional tools for studying UPRmt include fusion proteins of ATFS-1 and DVE-1, ATFS-1::GFP and DVE-1::GFP, key players of the UPRmt pathway. In this protocol, we discuss advantages and limitations of currently available methods and reporters, and we provide detailed instructions on how to image and quantify reporter expression.
    Keywords:  UPRmt reporters; atfs-1; dve-1; gfp; hsp-6; hsp-60
  16. J Clin Invest. 2022 Jan 04. pii: e148546. [Epub ahead of print]132(1):
      Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure. It discusses how this new understanding could add to the way we think about immunologic memory, vaccine development, and cancer immunotherapy.
  17. Front Pharmacol. 2021 ;12 768023
      Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing-based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington's disease, Friedreich's ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.
    Keywords:  European Medicines Agency (EMA); Food and Drug Administration (FDA, US); Friedreich’s ataxia; Huntington’s disease; amyotrophic lateral sclerosis; drug repurposing; orphanet; wolfram syndrome