bims-midmar 2022-01-02 papers

bims-midmar

Biomed News

on Mitochondrial DNA maintenance and replication

Issue of 2022–01–02
twelve papers selected by
Flavia Söllner, Ludwig-Maximilians University

Sperm mitochondrial DNA copy numbers in normal and abnormal semen analysis: a systematic review and meta-analysis.
Haplotype distribution in a forensic full mtDNA genome database of admixed Southern Brazilians and its association with self-declared ancestry and pigmentation traits.
The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression.
Oxidative stress induces Z-DNA binding protein 1-dependent activation of microglia via mtDNA released from retinal pigment epithelial cells.
Advanced approach for comprehensive mtDNA genome testing in mitochondrial disease.
Targeted delivery of PARP inhibitors to neuronal mitochondria via biomimetic engineered nanosystems in a mouse model of traumatic brain injury.
Baseline Characteristics of Mitochondrial DNA and Mutations Associated With Short-Term Posttreatment CD4+T-Cell Recovery in Chinese People With HIV.
Genome-wide association study of mitochondrial copy number.
Association Between Epilepsy and Leigh Syndrome With MT-ND3 Mutation, Particularly the m.10191T>C Point Mutation.
Charles Darwin's Mitochondrial Disorder: Possible Neuroendocrine Involvement.
Mitochondrial disease manifestations in relation to transcriptome location and function.
Episodic weakness and axonal sensorimotor neuropathy caused by a mitochondrial MT-ATP6 mutation.

BJOG. 2021 Dec 25.

Sperm mitochondrial DNA copy numbers in normal and abnormal semen analysis: a systematic review and meta-analysis.

Daria Popova, Priya Bhide, Francesco D'Antonio, Purusotam Basnet, Ganesh Acharya.

   BACKGROUND: Normal mature sperm have a considerably reduced number of mitochondria which provide the energy required for progressive sperm motility. Literature suggests that disorders of sperm motility may be linked to abnormal sperm mitochondrial number and function.
OBJECTIVES: To summarize the evidence from literature regarding the association of mitochondrial DNA copy numbers and semen quality with a particular emphasis on the spermatozoa motility.
SEARCH STRATEGY: Standard methodology recommended by Cochrane.
SELECTION CRITERIA: All published primary research reporting on the association between mitochondrial DNA copy numbers and semen quality.
DATA COLLECTION AND ANALYSIS: Using standard methodology recommended by Cochrane we pooled results using a random effects model and the findings were reported as a standardised mean difference.
MAIN RESULTS: We included 10 studies. The primary outcome was sperm mitochondrial DNA copy numbers. A meta-analysis including five studies showed significantly higher mitochondrial DNA copy numbers in abnormal semen analysis as compared to normal semen analysis(SMD 1.08, 95% CI 0.74-1.43). Seven studies included in the meta-analysis showed a significant negative correlation between mitochondrial DNA copy numbers and semen parameters. The quality of evidence was assessed as good to very good in 60% of studies.
CONCLUSIONS: Our review demonstrates significantly higher mitochondrial DNA in human sperm cells of men with abnormal semen analysis in comparison to men with normal semen analysis.

Keywords:  Mitochondrial DNA; abnormal semen parameters; sperm motility

DOI:  https://doi.org/10.1111/1471-0528.17078
Forensic Sci Int Genet. 2021 Dec 21. pii: S1872-4973(21)00185-X. [Epub ahead of print]57 102650

Haplotype distribution in a forensic full mtDNA genome database of admixed Southern Brazilians and its association with self-declared ancestry and pigmentation traits.

Eduardo Avila, Pietro Augusto Speransa, Catieli Gobetti Lindholz, Alessandro Kahmann, Clarice Sampaio Alho.

   BACKGROUND: The advent of massively parallel sequencing (MPS) applications focused on the generation of forensic-quality full mitochondrial genome sequences led to a popularization of the technique on a global scale. However, the lack of forensic-graded population databases has refrained a wider adoption of full genome sequences as the industry standard, despite its better discrimination capacity of individual maternal lineages.
PURPOSE: This work describes a forensic-oriented full mtDNA genome database comprised of 480 samples from a Southern Brazilian population.
METHODS: A collection of mitochondrial sequences were obtained from low-pass, full genome DNA sequencing results. The complete sample set was evaluated regarding haplotype composition and distribution. Summary statistics and forensic parameters were calculated and are presented for the database, with detailed information concerning the impact of removing genetic information in the form of specific variants or increasingly larger genomic regions. Interpopulational analysis comparing haplotypical diversity in Brazilian and 26 worldwide populations was also performed. The association between mitochondrial genetic variability and phenotypic diversity was also evaluated in populations, with self-declared ancestry and three distinct phenotypic pigmentation traits (eyes, skin and hair colors) as parameters.
RESULTS: The presented database can be used to evaluate mitochondrial-related genetic evidence, providing LR values of up to 20,465 for unobserved haplotypes. Haplotype distribution in Southern Brazil seems to be different than the remaining of the country, with a larger contribution of maternal lines with European origin. Despite association can be found between lighter and darker phenotypes or self-declared ancestry and haplotype distribution, prediction models cannot be reliably proposed due to the admixed nature of the Brazilian population.
CONCLUSIONS: The proposed database provides a basis for statistical calculation and frequency estimation of full mitochondrial genomes, and can be part of an integrated, representative, national database comprising most of the genetic diversity of maternal lineages in the country.

Keywords:  Database; Externally visible characteristics; Forensic; Full genome; Mitochondria; MtDNA; Pigmentation; Self-declared ancestry

DOI:  https://doi.org/10.1016/j.fsigen.2021.102650
Clin Transl Oncol. 2021 Dec 27.

The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression.

P A Bousquet, S Meltzer, A J Fuglestad, T Lüders, Y Esbensen, H V Juul, C Johansen, L G Lyckander, T Bjørnetrø, E M Inderberg, C Kersten, K R Redalen, A H Ree.

   PURPOSE: A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis.
PATIENTS AND METHODS: We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA.
RESULTS: Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation.
CONCLUSION: Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient's constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01816607; registration date: 22 March 2013.

Keywords:  CD4; Colorectal cancer; Immune cells; Metastasis; Mitochondrial DNA

DOI:  https://doi.org/10.1007/s12094-021-02756-w
J Biol Chem. 2021 Dec 22. pii: S0021-9258(21)01333-8. [Epub ahead of print] 101523

Oxidative stress induces Z-DNA binding protein 1-dependent activation of microglia via mtDNA released from retinal pigment epithelial cells.

Jamal Saada, Ryan J McAuley, Michela Marcatti, Tony Zifeng Tang, Massoud Motamedi, Bartosz Szczesny.

  Oxidative stress, inflammation, and aberrant activation of microglia in the retina are commonly observed in ocular pathologies. In glaucoma or age-related macular degeneration, the chronic activation of microglia affects retinal ganglion cells and photoreceptors, respectively, contributing to gradual vision loss. However, the molecular mechanisms that cause activation of microglia in the retina are not fully understood. Here we show that exposure of retinal pigment epithelial (RPE) cells to chronic low-level oxidative stress induces mitochondrial DNA (mtDNA)-specific damage, and the subsequent translocation of damaged mtDNA to the cytoplasm results in the binding and activation of intracellular DNA receptor Z-DNA binding protein 1 (ZBP1). Activation of the mtDNA/ZBP1 pathway triggers the expression of pro-inflammatory markers in RPE cells. In addition, we show the enhanced release of extracellular vesicles (EVs) containing fragments of mtDNA derived from the apical site of RPE cells induces a pro-inflammatory phenotype of microglia via activation of ZBP1 signaling. Collectively, our report establishes oxidatively damaged mtDNA as an important signaling molecule with ZBP1 as its intracellular receptor in the development of an inflammatory response in the retina. We propose that this novel mtDNA-mediated autocrine and paracrine mechanism for triggering and maintaining inflammation in the retina may play an important role in ocular pathologies. Therefore, the molecular mechanisms identified in this report are potentially suitable therapeutic targets to ameliorate development of ocular pathologies.

Keywords:  extracellular vesicles; microglia; mitochondrial DNA; oxidative stress; retinal pigment epithelial

DOI:  https://doi.org/10.1016/j.jbc.2021.101523
Mol Genet Metab. 2021 Dec 18. pii: S1096-7192(21)01191-4. [Epub ahead of print]

Advanced approach for comprehensive mtDNA genome testing in mitochondrial disease.

Jing Wang, Jorune Balciuniene, Maria Alejandra Diaz-Miranda, Elizabeth M McCormick, Erfan Aref-Eshghi, Alison M Muir, Kajia Cao, Juliana Troiani, Alicia Moseley, Zhiqian Fan, Zarazuela Zolkipli-Cunningham, Amy Goldstein, Rebecca D Ganetzky, Colleen C Muraresku, James T Peterson, Nancy B Spinner, Douglas C Wallace, Matthew C Dulik, Marni J Falk.

  Mitochondrial disease diagnosis requires interrogation of both nuclear and mitochondrial (mtDNA) genomes for single-nucleotide variants (SNVs) and copy number alterations, both in the proband and often maternal relatives, together with careful phenotype correlation. We developed a comprehensive mtDNA sequencing test ('MitoGenome') using long-range PCR (LR-PCR) to amplify the full length of the mtDNA genome followed by next generation sequencing (NGS) to accurately detect SNVs and large-scale mtDNA deletions (LSMD), combined with droplet digital PCR (ddPCR) for LSMD heteroplasmy quantification. Overall, MitoGenome tests were performed on 428 samples from 394 patients with suspected or confirmed mitochondrial disease. The positive yield was 11% (43/394), including 34 patients with pathogenic or likely pathogenic SNVs (the most common being m.3243A > G in 8/34 (24%) patients), 8 patients with single LSMD, and 3 patients with multiple LSMD exceeding 10% heteroplasmy levels. Two patients with both LSMD and pathogenic SNV were detected. Overall, this LR-PCR/NGS assay provides a highly accurate and comprehensive diagnostic method for simultaneous mtDNA SNV detection at heteroplasmy levels as low as 1% and LSMD detection at heteroplasmy levels below 10%. Inclusion of maternal samples for variant classification and ddPCR to quantify LSMD heteroplasmy levels further enables accurate pathogenicity assessment and clinical correlation interpretation of mtDNA genome sequence variants and copy number alterations.

Keywords:  Heteroplasmy; Mitochondrial genome; Multiple deletions; Single large-scale deletion; mtDNA mutation

DOI:  https://doi.org/10.1016/j.ymgme.2021.12.006
Acta Biomater. 2021 Dec 24. pii: S1742-7061(21)00830-8. [Epub ahead of print]

Targeted delivery of PARP inhibitors to neuronal mitochondria via biomimetic engineered nanosystems in a mouse model of traumatic brain injury.

Jiejie Sun, Jingzhou Liu, Chunhong Gao, Jinpeng Zheng, Jinbang Zhang, Yaning Ding, Wei Gong, Meiyan Yang, Zhiping Li, Yuli Wang, Yang Yang, Chunsheng Gao.

  Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co-modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. STATEMENT OF SIGNIFICANCE: TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane-coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo.

Keywords:  PARP inhibitor; Traumatic brain injury; nanostructured lipid carriers; neuronal mitochondria-targeting

DOI:  https://doi.org/10.1016/j.actbio.2021.12.023
Front Immunol. 2021 ;12 793375

Baseline Characteristics of Mitochondrial DNA and Mutations Associated With Short-Term Posttreatment CD4+T-Cell Recovery in Chinese People With HIV.

Anni Liu, Qian Wei, Haijiang Lin, Yingying Ding, Yan V Sun, Dan Zhao, Jiayu He, Zhonghui Ma, Feihu Li, Sujuan Zhou, Xiaoxiao Chen, Weiwei Shen, Meiyang Gao, Na He.

   Background: Mitochondrial DNA (mtDNA) profiles and contributions of mtDNA variants to CD4+T-cell recovery in Euramerican people living with HIV (PLWH) may not be transferred to East-Asian PLWH, highlighting the need to consider more regional studies. We aimed to identify mtDNA characteristics and mutations that explain the variability of short-term CD4+T-cell recovery in East-Asian PLWH.
Method: Eight hundred fifty-six newly reported antiretroviral therapy (ART)-naïve Chinese PLWH from the Comparative HIV and Aging Research in Taizhou (CHART) cohort (Zhejiang Province, Eastern China) were enrolled. MtDNA was extracted from peripheral whole blood of those PLWH at HIV diagnosis, amplified, and sequenced using polymerase chain reaction and gene array. Characterization metrics such as mutational diversity and momentum were developed to delineate baseline mtDNA mutational patterns in ART-naïve PLWH. The associations between mtDNA genome-wide single nucleotide variants and CD4+T-cell recovery after short-term (within ~48 weeks) ART in 724 PLWH were examined using bootstrapping median regressions.
Results: Of 856 participants, 74.18% and 25.82% were male and female, respectively. The median age was 37 years; 94.51% were of the major Han ethnicity, and 69.04% and 28.62% were of the heterosexual and homosexual transmission, respectively. We identified 2,352 types of mtDNA mutations and mtDNA regions D-loop, ND5, CYB, or RNR1 with highest mutational diversity or volume. Female PLWH rather than male PLWH at the baseline showed remarkable age-related uptrends of momentum and mutational diversity as well as correlations between CD4+T <200 (cells/μl) and age-related uptrends of mutational diversity in many mtDNA regions. After adjustments of important sociodemographic and clinical variables, m.1005T>C, m.1824T>C, m.3394T>C, m.4491G>A, m.7828A>G, m.9814T>C, m.10586G>A, m.12338T>C, m.13708G>A, and m.14308T>C (at the Bonferroni-corrected significance) were negatively associated with short-term CD4+T-cell recovery whereas m.93A>G, m.15218A>G, and m.16399A>G were positively associated with short-term CD4+T-cell recovery.
Conclusion: Our baseline mtDNA characterization stresses the attention to East-Asian female PLWH at risk of CD4+T-cell loss-related aging and noncommunicable chronic diseases. Furthermore, mtDNA variants identified in regression analyses account for heterogeneity in short-term CD4+T-cell recovery of East-Asian PLWH. These results may help individualize the East-Asian immune recovery strategies under complicated HIV management caused by CD4+T-cell loss.

Keywords:  ART; CD4+T cell; HIV; PLWH; mitochondrial DNA

DOI:  https://doi.org/10.3389/fimmu.2021.793375
Hum Mol Genet. 2021 Nov 23. pii: ddab341. [Epub ahead of print]

Genome-wide association study of mitochondrial copy number.

Manuel Gentiluomo, Matteo Giaccherini, Xīn Gào, Feng Guo, Hannah Stocker, Ben Schöttker, Hermann Brenner, Federico Canzian, Daniele Campa.

Mitochondrial DNA copy number (mtDNAcn) variation has been associated with increased risk of several human diseases in epidemiological studies. The quantification of mtDNAcn performed with real-time PCR is currently considered the de facto standard among several techniques. However, the heterogeneity of the laboratory methods (DNA extraction, storage, processing) used could give rise to results that are difficult to compare and reproduce across different studies. Several lines of evidence suggest that mtDNAcn is influenced by nuclear and mitochondrial genetic variability, however this relation is largely unexplored. The aim of this work was to elucidate the genetic basis of mtDNAcn variation. We performed a genome-wide association study (GWAS) of mtDNAcn in 6836 subjects from the ESTHER prospective cohort, and included, as replication set, the summary statistics of a GWAS that used 295 150 participants from the UK Biobank. We observed two novel associations with mtDNAcn variation on chromosome 19 (rs117176661), and 12 (rs7136238) that reached statistical significance at the genome-wide level. A polygenic score that we called mitoscore including all known single nucleotide polymorphisms explained 1.11% of the variation of mtDNAcn (p = 5.93 × 10-7). In conclusion, we performed a GWAS on mtDNAcn, adding to the evidence of the genetic background of this trait.

DOI: https://doi.org/10.1093/hmg/ddab341
Front Neurol. 2021 ;12 752467

Association Between Epilepsy and Leigh Syndrome With MT-ND3 Mutation, Particularly the m.10191T>C Point Mutation.

Ji-Hoon Na, Min Jung Lee, Chul Ho Lee, Young-Mock Lee.

  Background and Purpose: Recent advances in molecular genetic testing have led to a rapid increase in the understanding of the genetics of Leigh syndrome. Several studies have suggested that Leigh syndrome with MT-ND3 mutation is strongly associated with epilepsy. This study focused on the epilepsy-related characteristics of Leigh syndrome with MT-ND3 mutation identified in a single tertiary hospital in South Korea. Methods: We selected 31 patients with mitochondrial DNA (mtDNA) mutations who were genetically diagnosed with mtDNA-associated Leigh syndrome. Among them, seven patients with MT-ND3 mutations were detected. We reviewed various clinical findings such as laboratory findings, brain images, electroencephalography data, seizure types, seizure frequency, antiepileptic drug use history, and current seizure status. Results: The nucleotide changes in the seven patients with the Leigh syndrome with MT-ND3 mutation were divided into two groups: m.10191T>C and m.10158T>C. Six of the seven patients were found to have the m.10191T>C mutations. The median value of the mutant load was 82.5%, ranging from 57.9 to 93.6%. No particular tendency was observed for the first symptom or seizure onset or mutant load. The six patients with the m.10191T>C mutation were diagnosed with epilepsy. Three of these patients were diagnosed with Lennox-Gastaut syndrome (LGS). Conclusion: We reported a very strong association between epilepsy and MT-ND3 mutation in Leigh syndrome, particularly the m.10191T>C mutation. The possibility of an association between the epilepsy phenotype of the m.10191T>C mutation and LGS was noted.

Keywords:  Lennox-Gastaut syndrome; MT-ND3; epilepsy; m10191T>C; mitochondrial DNA-associated Leigh syndrome

DOI:  https://doi.org/10.3389/fneur.2021.752467
Cureus. 2021 Dec;13(12): e20689

Charles Darwin's Mitochondrial Disorder: Possible Neuroendocrine Involvement.

John Hayman, Josef Finsterer.

  Charles Darwin, the famous naturalist, suffered relapsing, debilitating illness for most of his adult life with a plethora of symptoms. The diagnosis favoured here for this illness is that of an adult-onset mitochondrial disorder due to a maternally inherited, pathological mitochondrial DNA mutation clinically manifesting as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome. This diagnosis accounts for Darwin's primary symptoms; in addition, it accounts for the various unusual illnesses that afflicted his siblings and maternal (Wedgwood) ancestors. Symptoms of Darwin's illness may be related to dysfunction of cells with high energy requirements; this includes cells constituting the cardiac conduction system, cerebral endothelial cells, neurons, neuroepithelial cells of the vestibular apparatus, and, as proposed here, central and peripheral neuroendocrine cells. Although Darwin's episodes of sudden facial flushing, his nocturnal panic attacks, and his severe gastrointestinal symptoms are not readily explained, these symptoms may relate to neuroendocrine dysfunction, either an uncontrolled release of stimulatory hormone or impaired inhibitory control. It is also conceivable that the autonomic system had been involved. A study of Darwin's illness may benefit those who suffer from similar symptoms today.

Keywords:  charles darwin’s illness; cyclic vomiting; functional abdominal pain syndrome; idiopathic flushing; melas syndrome; mitochondrial disorder; neuroendocrine dysfunction; panic disorder; serotonin; somatostatin

DOI:  https://doi.org/10.7759/cureus.20689
Mol Genet Metab. 2021 Dec 23. pii: S1096-7192(21)01193-8. [Epub ahead of print]

Mitochondrial disease manifestations in relation to transcriptome location and function.

Vikram Jakkamsetti, Seema Balasubramaniam, Nidhi Grover, Juan M Pascual.

  Localization within the nervous system provides context for neurological disease manifestations and treatment, with numerous disease mechanisms exhibiting predilect locations. In contrast, the molecular function of most disease-causing genes is generally considered dissociated from such brain regional correlations because most genes are expressed throughout the brain. We tested the factual basis for this dissociation by discerning between two distinct genetic disease mechanism possibilities: One, gene-specific, in which genetic disorders are poorly localizable because they are multiform at the molecular level, with each mutant gene acting more widely or complexly than via mere loss or gain of one function. The other, more general, where aspects shared by groups of genes such as membership in a gene set that sustains a concerted biological process accounts for a common or localizable phenotype. We analyzed mitochondrial substrate disorders as a paradigm of apparently heterogeneous diseases when considered from the point of view of their manifestations and individual function of their causal genes. We used publicly available transcriptomes, disease phenotypes published in peer-reviewed journals and Human Ontology classifications for 27 mitochondrial substrate metabolism diseases and analyzed if these disorders manifest common phenotypes and if this relates to common brain regions or cells as demarcated by their transcriptome. The most frequent phenotypic manifestations and brain structures involved were almost stereotypic regardless of the individual gene affected, correlating with the regional abundance of the transcriptome that served mitochondrial substrate metabolism. This also applied to the transcriptome of inhibitory neurons, which are dysfunctional in some mitochondrial diseases. This stands in contrast with resistance to dementia atrophy from other causes, which is known to also associate with greater expression of a similar fraction of the transcriptome. The results suggest that brain region or cell type dysfunction stemming from a broad process such as mitochondrial substrate metabolism is more relevant for disease manifestations than individual gene participation in specific molecular function.

Keywords:  Metabolism; Mitochondrial; Phenotype; Transcriptome

DOI:  https://doi.org/10.1016/j.ymgme.2021.12.008
J Formos Med Assoc. 2021 Dec 22. pii: S0929-6646(21)00536-2. [Epub ahead of print]

Episodic weakness and axonal sensorimotor neuropathy caused by a mitochondrial MT-ATP6 mutation.

Tzu-Hsuan Su, Ni-Chung Lee, Chao-Szu Wu, Steven Shinn-Forng Peng, Pi-Chuan Fan.

  Episodic weakness is typically associated with a group of disorders so called periodic paralyses. Their major causes are mutation of ion channels, and have rarely been linked to mitochondrial disorders. We report a 20-year-old man with episodic weakness and axonal sensorimotor neuropathy since the age of 10 years. Analysis of the next generation sequencing data of the entire mitochondrial genome extracted from the blood revealed a homoplasmic m.9185T > C variant in MT-ATP6. Acetazolamide may be responsive for episodic weakness, and supplements with l-carnitine with coenzyme-Q10 seem to be beneficial as well. To the best of our knowledge, this is the first report in Taiwan which reveals episodic weakness and sensorimotor polyneuropathy as a unique phenotype of MT-ATP6 mutations.

Keywords:  Episodic weakness; MT-ATP6 mutations; Mitochondrial disorders

DOI:  https://doi.org/10.1016/j.jfma.2021.12.003