bims-mitmed 2024-08-11 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024‒08‒11
thirteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

The clinical and genetic spectrum of mitochondrial diseases in China: A multicenter retrospective cross-sectional study.
Endocrine Disorders in Children with Primary Mitochondrial Diseases: Single-Center Experience.
Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level.
Analysis of Mitophagy Reporters in Drosophila.
Leigh Syndrome due to MT-ATP6 Variants: A Case Presentation and the Review of the Literature.
Placental mitochondrial impairment and its association with maternal metabolic dysfunction.
New and Emerging Drug and Gene Therapies for Friedreich Ataxia.
Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich ataxia.
The interplay between mitochondria, the gut microbiome and metabolites and their therapeutic potential in primary mitochondrial disease.
Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity.
Mitochondrial fragmentation in early differentiation of human MB135 myoblasts: Role of mitochondrial ROS production in the absence of depolarization.
Evolution and maintenance of mtDNA gene content across eukaryotes.

Clin Genet. 2024 Aug 09.

The clinical and genetic spectrum of mitochondrial diseases in China: A multicenter retrospective cross-sectional study.

Yang Zhao, Xutong Zhao, Kunqian Ji, Junling Wang, Yuying Zhao, Jie Lin, Qiang Gang, Meng Yu, Yun Yuan, Haishan Jiang, Chong Sun, Fang Fang, Chuanzhu Yan, Zhaoxia Wang.

  Mitochondrial diseases (MtDs) present diverse clinical phenotypes, yet large-scale studies are hindered by their rarity. This retrospective, multicenter study, conducted across five Chinese hospitals' neurology departments from 2009 to 2019, aimed to address this gap. Nationwide, 1351 patients were enrolled, with a median onset age of 14.0 (18.5) years. The predominant phenotype was mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (45.0%). Mitochondrial DNA (mtDNA) mutations were prevalent (87.4%), with m.3243A>G being the most common locus (48.7%). Meanwhile, POLG mutations in nuclear DNA (nDNA) accounted for 16.5%. Comparative analysis based on age groups (with a cut-off at 14 years) revealed the highest prevalence of MELAS, with Leigh syndrome (LS) and chronic progressive external ophthalmoplegia (CPEO) being the second most common phenotypes in junior and senior groups, respectively. Notably, the most commonly mutated nuclear genes varied across age groups. In conclusion, MELAS predominated in this Chinese MtD cohort, underscored by m.3243A>G and POLG as principal mtDNA mutations and pathogenic nuclear genes. The phenotypic and genotypic disparities observed among different age cohorts highlight the complex nature of MtDs.

Keywords:  genotype; heterogeneity; mitochondrial diseases; phenotype

DOI:  https://doi.org/10.1111/cge.14605
J Clin Res Pediatr Endocrinol. 2024 Aug 08.

Endocrine Disorders in Children with Primary Mitochondrial Diseases: Single-Center Experience.

Esra Deniz Papatya Çakır, Melike Ersıoy, Nihan Çakır Biçer, Asuman Gedikbaşı.

  Objective: Endocrine abnormalities may represent the only clinical manifestation of primary mitochondrial disorders. This study aimed to evaluate the endocrinological characteristics of mitochondrial disease in our cohort.Methods: A total of twenty-six pediatric patients diagnosed with mitochondrial disease were categorized on the basis of their specific genetic abnormalities. The auxologic data, pubertal development, and, based on their clinical symptoms, hormonal profiles were obtained.
Results: Twelve of the cohort of 26 patients (46%) were female. In 15 of the patients (57.6%), their mitochondrial disease (MD) was caused by nuclear DNA mutations (nDNA group). Four patients had Leigh syndrome, 2 patients had LHON syndrome, 2 patients had MELAS, and 1 patient had KSS clinical phenotype. The median age at diagnosis was 2.91 (0.59-16.8) years, and the median age at first endocrinologic evaluation was 4.62 (1.26-18) years. The mean height SDS was -1.34 ± 2.12, and the mean BMI SDS was -0.82 ± 1.96 for all patients. Of the 26 patients, 6 (23%) had a range of hormonal deficits. Ovarian insufficiency, central adrenal insufficiency, central hypothyroidism, diabetes mellitus, and critical illness-related adrenal insufficiency were all observed. Three of the patients were initially monitored in the endocrine clinic for hormone deficiencies but it was later determined that the hormonal abnormalities were caused by underlying mitochondrial disease.
Conclusion: Individuals diagnosed with mitochondrial disease, particularly those with specific genetic abnormalities, are considered a high-risk group for developing hormonal deficits. Endocrine diseases could be one of the primary mitochondrial disorders' early warning symptoms.

Keywords:  Endocrin abnormalities; Endocrine disorders; Primary mitochondrial disease; genotype-phenotype

DOI:  https://doi.org/10.4274/jcrpe.galenos.2024.2024-1-11
EMBO J. 2024 Aug 05.

Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level.

Rodaria Roussou, Dirk Metzler, Francesco Padovani, Felix Thoma, Rebecca Schwarz, Boris Shraiman, Kurt M Schmoller, Christof Osman.

  Mitochondrial DNA (mtDNA) is present in multiple copies within cells and is required for mitochondrial ATP generation. Even within individual cells, mtDNA copies can differ in their sequence, a state known as heteroplasmy. The principles underlying dynamic changes in the degree of heteroplasmy remain incompletely understood, due to the inability to monitor this phenomenon in real time. Here, we employ mtDNA-based fluorescent markers, microfluidics, and automated cell tracking, to follow mtDNA variants in live heteroplasmic yeast populations at the single-cell level. This approach, in combination with direct mtDNA tracking and data-driven mathematical modeling reveals asymmetric partitioning of mtDNA copies during cell division, as well as limited mitochondrial fusion and fission frequencies, as critical driving forces for mtDNA variant segregation. Given that our approach also facilitates assessment of segregation between intact and mutant mtDNA, we anticipate that it will be instrumental in elucidating the mechanisms underlying the purifying selection of mtDNA.

Keywords:  Heteroplasmy; Mathematical Modeling; Mitochondria; Mitochondrial Fission; mtDNA

DOI:  https://doi.org/10.1038/s44318-024-00183-5
Methods Mol Biol. 2024 ;2845 79-93

Analysis of Mitophagy Reporters in Drosophila.

Alvaro Sanchez-Martinez, Aitor Martinez, Alexander J Whitworth.

  Mitophagy is the degradation of mitochondria via the autophagy-lysosome system, disruption of which has been linked to multiple neurodegenerative diseases. As a flux process involving the identification, tagging, and degradation of subcellular components, the analysis of mitophagy benefits from the microscopy analysis of fluorescent reporters. Studying the pathogenic mechanisms of disease also benefits from analysis in animal models in order to capture the complex interplay of molecular and cell biological phenomena. Here, we describe protocols to analyze mitophagy reporters in Drosophila by light microscopy.

Keywords:  Brain; Drosophila; Light microscopy; Mitochondria; Mitophagy; Muscle; Neurodegeneration; Reporter; mito-QC; mtx-QC

DOI:  https://doi.org/10.1007/978-1-0716-4067-8_7
Mol Syndromol. 2024 Aug;15(4): 333-338

Leigh Syndrome due to MT-ATP6 Variants: A Case Presentation and the Review of the Literature.

Halil Tuna Akar, Esra Sayar, Özlem Sarıtaş Nakip, Esra Sönmez, Mehmet Burak Özkan, Asburçe Olgaç.

  Introduction: Leigh syndrome is a rare mitochondrial disorder characterized by subacute necrotizing encephalomyelopathy, resulting from defects in mitochondrial respiratory enzymes or pyruvate dehydrogenase complex. Symptoms can manifest in infancy, childhood, or adulthood. We present a case of a 7-month-old girl initially misdiagnosed with septic shock but was later found to have Leigh encephalomyelopathy due to MT-ATP6 deficiency.Case Presentation: A 7-month-old girl was admitted with fever, drowsiness, and wheezing, initially diagnosed with septic shock. She had a history of parental consanguinity and hypotonia. Physical examination revealed unconsciousness, miotic pupils, and respiratory distress. Initial laboratory tests showed significant metabolic acidosis and elevated lactate, creatine kinase, and ammonia levels. The patient was treated for sepsis and shock, but her condition worsened with elevated lactate and liver transaminases, eventually leading to hypertrophic cardiomyopathy and multiorgan failure. Her basic metabolic scans showed extremely low citrulline levels, whole-exome sequencing analysis did not show any pathologic change in nuclear genome, and mitochondrial genome analysis revealed an MT-ATP homoplasmic variant. She passed away on the 22nd day of hospitalization.
Discussion/Conclusion: While mitochondrial disorders are broadly acknowledged for their phenotypic diversity, it is essential to note that specific disorders, such as Leigh syndrome, display distinctive presentations with varying degrees of severity. Factors such as the percentage of homoplasmy contribute to the variability in manifestations. Notably, MT-ATP6-associated Leigh syndrome is predominantly characterized by an early onset, typically occurring before the age of 2 years. Low citrulline levels have been observed in approximately 90% of patients with MT-ATP6-related disorders, distinguishing them from other mitochondrial disorders. The exact mechanisms underlying this specific metabolic alteration are not fully understood, but it could be linked to disruptions in the mitochondrial energy production process. The mitochondria are essential for various metabolic pathways, including the urea cycle, where citrulline is involved. The association between low citrulline levels and MT-ATP6-related disorders raises the possibility of using citrulline as a potential biomarker for disease identification. MT-ATP6 defects should be kept in mind in cases with mitochondrial disease and low plasma citrulline levels.

Keywords:  Inborn errors of metabolism; Leigh’s syndrome; Mitochondrial disorders

DOI:  https://doi.org/10.1159/000536676
J Physiol. 2024 Aug 08.

Placental mitochondrial impairment and its association with maternal metabolic dysfunction.

Adriana Grismaldo R, Luis A Luévano-Martínez, Monserrat Reyes, Grecia García-Márquez, Gerardo García-Rivas, Luis Sobrevia.

  The placenta plays an essential role in pregnancy, leading to proper fetal development and growth. As an organ with multiple physiological functions for both mother and fetus, it is a highly energetic and metabolically demanding tissue. Mitochondrial physiology plays a crucial role in the metabolism of this organ and thus any alteration leading to mitochondrial dysfunction has a severe outcome in the development of the fetus. Pregnancy-related pathological states with a mitochondrial dysfunction outcome include preeclampsia and gestational diabetes mellitus. In this review, we address the role of mitochondrial morphology, metabolism and physiology of the placenta during pregnancy, highlighting the roles of the cytotrophoblast and syncytiotrophoblast. We also describe the relationship between preeclampsia, gestational diabetes, gestational diabesity and pre-pregnancy maternal obesity with mitochondrial dysfunction.

Keywords:  gestational diabetes; metabolic dysfunction; mitochondria; obesity; placenta; preeclampsia; pregnancy

DOI:  https://doi.org/10.1113/JP285935
CNS Drugs. 2024 Aug 08.

New and Emerging Drug and Gene Therapies for Friedreich Ataxia.

Varlli Scott, Martin B Delatycki, Geneieve Tai, Louise A Corben.

The life shortening nature of Friedreich Ataxia (FRDA) demands the search for therapies that can delay, stop or reverse its relentless trajectory. This review provides a contemporary position of drug and gene therapies for FRDA currently in phase 1 clinical trials and beyond. Despite significant scientific advances in the specificity of both compounds and targets developed and investigated, challenges remain for the advancement of treatments in a limited recruitment population. Currently therapies focus on reducing oxidative stress and improving mitochondrial function, modulating frataxin controlled metabolic pathways and gene replacement and editing. Approval of omaveloxolone, the first treatment for individuals with FRDA aged 16 years and over, has created much excitement for both those living with FRDA and those that care for them. The process of approval of omaveloxolone by the US Food and Drug Administration highlighted the importance of sensitive outcome measures and the significant role of data from natural history studies.

DOI: https://doi.org/10.1007/s40263-024-01113-z
Neurobiol Dis. 2024 Aug 05. pii: S0969-9961(24)00231-6. [Epub ahead of print] 106631

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich ataxia.

Andrés Vicente-Acosta, Saúl Herranz-Martín, María Ruth Pazos, Jorge Galán-Cruz, Mario Amores, Frida Loria, Javier Díaz-Nido.

  Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the FXN gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, which are some of the main symptoms observed in affected individuals. Like in other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in patients with Friedreich ataxia. In this work, we followed and characterized the progression of changes in the cerebellar cortex in the latest version of Friedreich ataxia humanized mouse model, YG8-800 (Fxnnull:YG8s(GAA)>800), which carries a human FXN transgene containing >800 GAA repeats. Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between the control strain Y47R and YG8-800 mice at different time points. Our findings revealed that YG8-800 mice exhibit an ataxic phenotype characterized by poor motor coordination, decreased body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration, as was increased expression of key proinflammatory cytokines and downregulation of neurotrophic factors. Together, our results show that the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.

Keywords:  Cerebellum; Frataxin; Friedreich ataxia; Glial cells; Neurodegeneration

DOI:  https://doi.org/10.1016/j.nbd.2024.106631
Front Pharmacol. 2024 ;15 1428242

The interplay between mitochondria, the gut microbiome and metabolites and their therapeutic potential in primary mitochondrial disease.

Kassandra A Zachos, Jann Aldrin Gamboa, Aleena S Dewji, Jocelyn Lee, Sonya Brijbassi, Ana C Andreazza.

  The various roles of the mitochondria and the microbiome in health and disease have been thoroughly investigated, though they are often examined independently and in the context of chronic disease. However, the mitochondria and microbiome are closely connected, namely, through their evolution, maternal inheritance patterns, overlapping role in many diseases and their importance in the maintenance of human health. The concept known as the "mitochondria-microbiome crosstalk" is the ongoing bidirectional crosstalk between these two entities and warrants further exploration and consideration, especially in the context of primary mitochondrial disease, where mitochondrial dysfunction can be detrimental for clinical manifestation of disease, and the role and composition of the microbiome is rarely investigated. A potential mechanism underlying this crosstalk is the role of metabolites from both the mitochondria and the microbiome. During digestion, gut microbes modulate compounds found in food, which can produce metabolites with various bioactive effects. Similarly, mitochondrial metabolites are produced from substrates that undergo biochemical processes during cellular respiration. This review aims to provide an overview of current literature examining the mitochondria-microbiome crosstalk, the role of commonly studied metabolites serve in signaling and mediating these biochemical pathways, and the impact diet has on both the mitochondria and the microbiome. As a final point, this review highlights the up-to-date implications of the mitochondria-microbiome crosstalk in mitochondrial disease and its potential as a therapeutic tool or target.

Keywords:  diet; microbiome; mitochondria; mitochondria-microbiome crosstalk; mitochondrial disease

DOI:  https://doi.org/10.3389/fphar.2024.1428242
Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00278-X. [Epub ahead of print]

Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.

Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J DeBosch.

  Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.

Keywords:  arginase; diabetes; fasting; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; nicotinamide adenine dinucleotide; nicotinamide riboside; obesity; tricarboxylic acid cycle; urea cycle

DOI:  https://doi.org/10.1016/j.cmet.2024.07.007
Cell Mol Life Sci. 2024 Aug 09. 81(1): 340

Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity.

Saiya Zhu, Yangyang Niu, Wenqian Zhou, Yuqing Liu, Jing Liu, Xi Liu, Limin Lu, Chen Yu.

  Copper is a trace element essential for numerous biological activities, whereas the mitochondria serve as both major sites of intracellular copper utilization and copper reservoir. Here, we investigated the impact of mitochondrial copper overload on the tricarboxylic acid cycle, renal senescence and fibrosis. We found that copper ion levels are significantly elevated in the mitochondria in fibrotic kidney tissues, which are accompanied by reduced pyruvate dehydrogenase (PDH) activity, mitochondrial dysfunction, cellular senescence and renal fibrosis. Conversely, lowering mitochondrial copper levels effectively restore PDH enzyme activity, improve mitochondrial function, mitigate cellular senescence and renal fibrosis. Mechanically, we found that mitochondrial copper could bind directly to lipoylated dihydrolipoamide acetyltransferase (DLAT), the E2 component of the PDH complex, thereby changing the interaction between the subunits of lipoylated DLAT, inducing lipoylated DLAT protein dimerization, and ultimately inhibiting PDH enzyme activity. Collectively, our study indicates that mitochondrial copper overload could inhibit PDH activity, subsequently leading to mitochondrial dysfunction, cellular senescence and renal fibrosis. Reducing mitochondrial copper overload might therefore serve as a strategy to rescue renal fibrosis.

Keywords:  Copper; Mitochondria; Pyruvate dehydrogenase; Renal fibrosis; Tricarboxylic acid (TCA) cycle

DOI:  https://doi.org/10.1007/s00018-024-05358-1
Life Sci. 2024 Aug 02. pii: S0024-3205(24)00531-9. [Epub ahead of print]354 122941

Mitochondrial fragmentation in early differentiation of human MB135 myoblasts: Role of mitochondrial ROS production in the absence of depolarization.

Daniil A Chernyavskij, Konstantin G Lyamzaev, Olga Yu Pletjushkina, Fei Chen, Anna Karpukhina, Yegor S Vassetzky, Boris V Chernyak, Ekaterina N Popova.

  AIMS: Study of the role of mitochondria-generated reactive oxygen species (mtROS) and mitochondrial polarization in mitochondrial fragmentation at the initial stages of myogenesis.MAIN METHODS: Mitochondrial morphology, Drp1 protein phosphorylation, mitochondrial electron transport chain components content, mtROS and mitochondrial lipid peroxidation levels, and mitochondrial polarization were evaluated on days 1 and 2 of human MB135 myoblasts differentiation. A mitochondria-targeted antioxidant SkQ1 was used to elucidate the effect of mtROS on mitochondria.
KEY FINDINGS: In immortalized human MB135 myoblasts, mitochondrial fragmentation began on day 1 of differentiation before the myoblast fusion. This fragmentation was preceded by dephosphorylation of p-Drp1 (Ser-637). On day 2, an increase in the content of some mitochondrial proteins was observed, indicating mitochondrial biogenesis stimulation. Furthermore, we found that myogenic differentiation, even on day 1, was accompanied both by an increased production of mtROS, and lipid peroxidation of the inner mitochondrial membrane. SkQ1 blocked these effects and partially reduced the level of mitochondrial fragmentation, but did not affect the dephosphorylation of p-Drp1 (Ser-637). Importantly, mitochondrial fragmentation at early stages of MB135 differentiation was not accompanied by depolarization, as an important stimulus for mitochondrial fragmentation.
SIGNIFICANCE: Mitochondrial fragmentation during early myogenic differentiation depends on mtROS production rather than mitochondrial depolarization. SkQ1 only partially inhibited mitochondrial fragmentation, without significant effects on mitophagy or early myogenic differentiation.

Keywords:  Mitochondrial fragmentation; Mitochondrial membrane potential (ΔΨm); Mitochondrial reactive oxygen species (mtROS); Myogenesis; Myogenic differentiation

DOI:  https://doi.org/10.1016/j.lfs.2024.122941
Biochem J. 2024 Aug 07. 481(15): 1015-1042

Evolution and maintenance of mtDNA gene content across eukaryotes.

Shibani Veeraragavan, Maria Johansen, Iain G Johnston.

  Across eukaryotes, most genes required for mitochondrial function have been transferred to, or otherwise acquired by, the nucleus. Encoding genes in the nucleus has many advantages. So why do mitochondria retain any genes at all? Why does the set of mtDNA genes vary so much across different species? And how do species maintain functionality in the mtDNA genes they do retain? In this review, we will discuss some possible answers to these questions, attempting a broad perspective across eukaryotes. We hope to cover some interesting features which may be less familiar from the perspective of particular species, including the ubiquity of recombination outside bilaterian animals, encrypted chainmail-like mtDNA, single genes split over multiple mtDNA chromosomes, triparental inheritance, gene transfer by grafting, gain of mtDNA recombination factors, social networks of mitochondria, and the role of mtDNA dysfunction in feeding the world. We will discuss a unifying picture where organismal ecology and gene-specific features together influence whether organism X retains mtDNA gene Y, and where ecology and development together determine which strategies, importantly including recombination, are used to maintain the mtDNA genes that are retained.

Keywords:  genome evolution; mitochondrial evolution; mtDNA

DOI:  https://doi.org/10.1042/BCJ20230415