bims-mitmed 2024-06-09 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024‒06‒09
twenty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Status epilepticus in POLG disease: a large multinational study.
Mini-encyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care-clinically relevant 3PM innovation.
Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.
Senescent glia link mitochondrial dysfunction and lipid accumulation.
Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.
Structural basis for human mitochondrial tRNA maturation.
Mitophagy in relation to chronic inflammation/ROS in aging.
A zebrafish tufm mutant model for the COXPD4 syndrome of aberrant mitochondrial function.
Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.
Genotype and Phenotype Characteristics of 58 Cases of Mitochondrial Epilepsy with Nuclear DNA Mutations in Children.
Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery.
Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
A novel homozygous pathogenic missense variant in COX6B1: Further delineation of the phenotype.
Late-Onset Leigh Syndrome With Protracted Gastrointestinal Manifestations: A Rare Case Report.
Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
An enigmatic pedigree of variable presentations of optic neuropathy due to mitochondrial-ND6 mutation.
Long non-coding RNA TUG1 is downregulated in Friedreich's ataxia.
Liver mitochondrial coupling efficiency and its relationship to oxidative capacity and adenine nucleotide translocase content: A comparative study among crocodiles, birds and mammals.
TRABD modulates mitochondrial homeostasis and tissue integrity.
Lysosomal control of the cGAS-STING signaling.
Mitochondrial lipidomes are tissue specific - low cholesterol contents relate to UCP1 activity.
Mitochondrial mechanisms in the pathogenesis of chronic inflammatory musculoskeletal disorders.
Safety and efficacy of platelet-derived mitochondrial transplantation in ischaemic heart disease.
Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
Personalized metabolic whole-body models for newborns and infants predict growth and biomarkers of inherited metabolic diseases.
Aberrant PGC-1α signaling in a lamb model of persistent pulmonary hypertension of the newborn.

J Neurol. 2024 Jun 01.

Status epilepticus in POLG disease: a large multinational study.

Omar Hikmat, Karin Naess, Martin Engvall, Claus Klingenberg, Magnhild Rasmussen, Eylert Brodtkorb, Elsebet Ostergaard, Irenaeus de Coo, Leticia Pias-Peleteiro, Pirjo Isohanni, Johanna Uusimaa, Kari Majamaa, Mikko Kärppä, Juan Dario Ortigoza-Escobar, Trine Tangeraas, Siren Berland, Emma Harrison, Heather Biggs, Rita Horvath, Niklas Darin, Shamima Rahman, Laurence A Bindoff.

  We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE.

Keywords:   POLG ; Epilepsy; Mitochondrial disease; Refractory status epilepticus

DOI:  https://doi.org/10.1007/s00415-024-12463-5
EPMA J. 2024 Jun;15(2): 163-205

Mini-encyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care-clinically relevant 3PM innovation.

Olga Golubnitschaja, Andrea Kapinova, Nafiseh Sargheini, Bianka Bojkova, Marko Kapalla, Luisa Heinrich, Eleni Gkika, Peter Kubatka.

  Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.

Keywords:  Allicin; Aloe vera; Alpha-lipoic acid; Apigenin; Biological age; Carnitine; Catechins; CoQ10; Creatine; Curcumin; DMG-gold; Fisetin; Ginkgo biloba; Ginseng; Green tea; Health protection; Kaempferol; L-Carnosine; Life quality; Longevity; Melatonin; Mitochondria-targeted substances; Mitochondrial health; Mitophagy; Nutrients; Octacosanol; Oleanolic acid; PQQ; Phytomedicine; Piperlongumine; Predictive preventive personalized medicine (PPPM / 3PM); Primary and Secondary care; Pterostilbene; Quercetin; Resveratrol; Saffron; Senolytics; Senomorphics; Senotherapeutics; Silibinin; Sirtuins; Trehalose; Vitamin B; Vitamin D

DOI:  https://doi.org/10.1007/s13167-024-00358-4
Mol Cell Biol. 2024 Jun 03. 1-19

Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.

Jordan J Crameri, Catherine S Palmer, Tegan Stait, Thomas D Jackson, Matthew Lynch, Adriane Sinclair, Leah E Frajman, Alison G Compton, David Coman, David R Thorburn, Ann E Frazier, Diana Stojanovski.

  TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.

Keywords:  Mitochondria; TIM23 complex; TIMM50; mitochondrial disease; mitochondrial protein import

DOI:  https://doi.org/10.1080/10985549.2024.2353652
Nature. 2024 Jun 05.

Senescent glia link mitochondrial dysfunction and lipid accumulation.

China N Byrns, Alexandra E Perlegos, Karl N Miller, Zhecheng Jin, Faith R Carranza, Palak Manchandra, Connor H Beveridge, Caitlin E Randolph, V Sai Chaluvadi, Shirley L Zhang, Ananth R Srinivasan, F C Bennett, Amita Sehgal, Peter D Adams, Gaurav Chopra, Nancy M Bonini.

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.

DOI: https://doi.org/10.1038/s41586-024-07516-8
Ann Med Surg (Lond). 2024 Jun;86(6): 3753-3756

Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.

Azita Tavasoli, Maryam Kachuei, Saeed Talebi, Shayan Eghdami.

  Introduction and importance: Cytochrome C oxidase (COX) deficiency is an uncommon inherited metabolic disorder. It is identified by a lack of the COX, also known as Complex IV. This enzyme plays a crucial role in the rate-limiting and oxygen-accepting step of the respiratory chain within the subcellular structures called mitochondria. The deficiency of COX can either be restricted to skeletal muscle tissues or can impact multiple tissues throughout the body.Case presentation: A 3-year-old girl was admitted due to muscle weakness and a decline in developmental milestones 7 days after a significant stressor. Leukodystrophy was observed in the brain magnetic resonance imaging, and genome sequencing identified a homozygous mutation in exon 1 and 7 of chromosome 17. This mutation led to a deficiency in COX10, which is a component of mitochondrial complex IV.
Clinical discussion: In the medical field, inherited metabolic disorders can be complex to diagnose due to overlapping symptoms with other conditions. Mitochondria's oxidative phosphorylation system, including the COX enzyme complex, plays a crucial role in energy production. Mitochondrial disorders, including COX deficiency, can present at various stages of life with diverse symptoms. Treatment options focus on supportive care and potential benefits from supplements like coenzyme-Q10 and small-molecule therapies targeting mitochondrial function. Identifying genetic mutations is key for advancing treatments in this area.
Conclusion: This report presents a unique case of developmental regression and muscle weakness in a paediatric patient, which can be attributed to a rare occurrence of type 3 nuclear mitochondrial complex IV deficiency.

Keywords:  COX10; case report; cytochrome c oxidase deficiency; mitochondrial complex IV; mitochondrial disorder

DOI:  https://doi.org/10.1097/MS9.0000000000002096
Nat Commun. 2024 Jun 01. 15(1): 4683

Structural basis for human mitochondrial tRNA maturation.

Vincent Meynier, Steven W Hardwick, Marjorie Catala, Johann J Roske, Stephanie Oerum, Dimitri Y Chirgadze, Pierre Barraud, Wyatt W Yue, Ben F Luisi, Carine Tisné.

The human mitochondrial genome is transcribed into two RNAs, containing mRNAs, rRNAs and tRNAs, all dedicated to produce essential proteins of the respiratory chain. The precise excision of tRNAs by the mitochondrial endoribonucleases (mt-RNase), P and Z, releases all RNA species from the two RNA transcripts. The tRNAs then undergo 3'-CCA addition. In metazoan mitochondria, RNase P is a multi-enzyme assembly that comprises the endoribonuclease PRORP and a tRNA methyltransferase subcomplex. The requirement for this tRNA methyltransferase subcomplex for mt-RNase P cleavage activity, as well as the mechanisms of pre-tRNA 3'-cleavage and 3'-CCA addition, are still poorly understood. Here, we report cryo-EM structures that visualise four steps of mitochondrial tRNA maturation: 5' and 3' tRNA-end processing, methylation and 3'-CCA addition, and explain the defined sequential order of the tRNA processing steps. The methyltransferase subcomplex recognises the pre-tRNA in a distinct mode that can support tRNA-end processing and 3'-CCA addition, likely resulting from an evolutionary adaptation of mitochondrial tRNA maturation complexes to the structurally-fragile mitochondrial tRNAs. This subcomplex can also ensure a tRNA-folding quality-control checkpoint before the sequential docking of the maturation enzymes. Altogether, our study provides detailed molecular insight into RNA-transcript processing and tRNA maturation in human mitochondria.

DOI: https://doi.org/10.1038/s41467-024-49132-0
Mol Cell Biochem. 2024 Jun 04.

Mitophagy in relation to chronic inflammation/ROS in aging.

Liang Kong, Shuhao Li, Yu Fu, Qinyun Cai, Xinyun Du, Jingyan Liang, Tan Ma.

  Various assaults on mitochondria occur during the human aging process, contributing to mitochondrial dysfunction. This mitochondrial dysfunction is intricately connected with aging and diseases associated with it. In vivo, the accumulation of defective mitochondria can precipitate inflammatory and oxidative stress, thereby accelerating aging. Mitophagy, an essential selective autophagy process, plays a crucial role in managing mitochondrial quality control and homeostasis. It is a highly specialized mechanism that systematically removes damaged or impaired mitochondria from cells, ensuring their optimal functioning and survival. By engaging in mitophagy, cells are able to maintain a balanced and stable environment, free from the potentially harmful effects of dysfunctional mitochondria. An ever-growing body of research highlights the significance of mitophagy in both aging and age-related diseases. Nonetheless, the association between mitophagy and inflammation or oxidative stress induced by mitochondrial dysfunction remains ambiguous. We review the fundamental mechanisms of mitophagy in this paper, delve into its relationship with age-related stress, and propose suggestions for future research directions.

Keywords:  Aging; Chronic inflammation; Mitophagy; ROS

DOI:  https://doi.org/10.1007/s11010-024-05042-9
J Genet Genomics. 2024 May 31. pii: S1673-8527(24)00122-X. [Epub ahead of print]

A zebrafish tufm mutant model for the COXPD4 syndrome of aberrant mitochondrial function.

Ting Li, Tursunjan Aziz, Guangyuan Li, Lin Zhang, Jihua Yao, Shunji Jia.

  Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy. Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4 (COXPD4), a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain (MRC) complexes. The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management. In this study, we construct a zebrafish tufm-/- mutant that closely resembles the COXPD4 syndrome, exhibiting compromised mitochondrial protein translation, dysfunctional mitochondria with oxidative phosphorylation (OXPHOS) defects, and significant metabolic suppression of the tricarboxylic acid (TCA) cycle. Leveraging this COXPD4 zebrafish model, we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4. Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.

Keywords:  COXPD4; Disease model; Mitochondria; Tufm; Zebrafish

DOI:  https://doi.org/10.1016/j.jgg.2024.05.009
Sci Adv. 2024 Jun 07. 10(23): eadn7191

Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.

Olawale G Raimi, Hina Ojha, Kenneth Ehses, Verena Dederer, Sven M Lange, Cristian Polo Rivera, Tom D Deegan, Yinchen Chen, Melanie Wightman, Rachel Toth, Karim P M Labib, Sebastian Mathea, Neil Ranson, Rubén Fernández-Busnadiego, Miratul M K Muqit.

Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson's disease (PD). Stabilization of PINK1 at the translocase of outer membrane (TOM) complex of damaged mitochondria is critical for its activation. The mechanism of how PINK1 is activated in the TOM complex is unclear. Here, we report that co-expression of human PINK1 and all seven TOM subunits in Saccharomyces cerevisiae is sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit toward PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modeling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These findings will aid in the development of small-molecule activators of PINK1 as a therapeutic strategy for PD.

DOI: https://doi.org/10.1126/sciadv.adn7191
Neurol Sci. 2024 Jun 04.

Genotype and Phenotype Characteristics of 58 Cases of Mitochondrial Epilepsy with Nuclear DNA Mutations in Children.

Xiaodi Han, Hua Li, Jie Deng, Xiuwei Zhuo, Zhimei Liu, Manting Xu, Weixing Feng, Shuhua Chen, Fang Fang.

  OBJECTIVE: Identify the genotype and clinical characteristics of mitochondrial epilepsy caused by nDNA mutations in Chinese children and explore the treatment and prognosis of the condition.STUDY DESIGN: This is a retrospective cohort study conducted at a single center, including patients diagnosed with an established nDNA mutation-associated primary mitochondrial disease between October 2012 and March 2023 who also met the practical clinical definition of epilepsy published by the ILAE in 2014.
RESULTS: Of the 58 patients identified, 74.1% had an onset before the age of 1 year and 63.8% had seizures as their initial symptom. Developmental and epileptic encephalopathy (DEE) (31%) are the most common phenotypes. The most frequently observed MRI abnormalities include abnormal signal asymmetry in the bilateral basal ganglia and/or brainstem (34.7%), as well as brain atrophy, myelin sheath dysplasia, and corpus callosum dysplasia (32.7%). Of the 40 patients followed, seizure treatment was effective in 18 of the cases, while it was ineffective in 22. The mitochondrial DNA depletion syndrome (MDS) was found to be more difficult to control seizures than other phenotypes (P < 0.05). Additionally, the MDS was associated with a significantly higher mortality rate compared to alternative phenotypes (P < 0.05).
CONCLUSIONS: The onset of mitochondrial epilepsy due to nDNA mutations is early and seizures are the most common initial symptom. DEE is the most common phenotype. Characteristic MRI abnormalities in the brain may be helpful in the diagnosis of primary mitochondrial disease. People with MDS typically face challenges in seizure control and have a poor prognosis.

Keywords:  Children; Epilepsy; Nuclear DNA; Primary mitochondrial disease

DOI:  https://doi.org/10.1007/s10072-024-07586-6
Adv Drug Deliv Rev. 2024 Jun 05. pii: S0169-409X(24)00177-7. [Epub ahead of print] 115355

Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery.

Yi Wang, Jing-Song Yang, Min Zhao, Jia-Qi Chen, Hai-Xin Xie, Hao-Yuan Yu, Na-Hui Liu, Zi-Juan Yi, Hui-Lin Liang, Lei Xing, Hu-Lin Jiang.

  Mitochondrial genome (mtDNA) independent of nuclear gene is a set of double-stranded circular DNA that encodes 13 proteins, 2 ribosomal RNAs and 22 mitochondrial transfer RNAs, all of which play vital roles in functions as well as behaviors of mitochondria. Mutations in mtDNA result in various mitochondrial disorders without available cures. However, the manipulation of mtDNA via the mitochondria-targeted gene delivery faces formidable barriers, particularly owing to the mitochondrial double membrane. Given the fact that there are various transport channels on the mitochondrial membrane used to transfer a variety of endogenous substances to maintain the normal functions of mitochondria, mitochondrial endogenous substance transport-inspired nanomaterials have been proposed for mitochondria-targeted gene delivery. In this review, we summary mitochondria-targeted gene delivery systems based on different mitochondrial endogenous substance transport pathways. These are categorized into mitochondrial steroid hormones import pathways-inspired nanomaterials, protein import pathways-inspired nanomaterials and other mitochondria-targeted gene delivery nanomaterials. We also review the applications and challenges involving in current mitochondrial gene editing systems. This review delves into the approaches of mitochondria-targeted gene delivery, providing detail on the design of mitochondria-targeted delivery systems and limitations regarding the varying technologies. Despite the progress in this field is currently slow, the ongoing exploration of mitochondrial endogenous substance transport and mitochondrial biological phenomena may act as a crucial breakthrough in the targeted delivery of gene into mitochondria and even the manipulation of mtDNA.

Keywords:  Drug delivery system; Gene delivery; Mitochondrial endogenous transport; Mitochondrial genome; Nanomaterials

DOI:  https://doi.org/10.1016/j.addr.2024.115355
Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00178-5. [Epub ahead of print]36(6): 1394-1410.e12

Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.

Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R Keshari.

  A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.

Keywords:  brain; glucose; imaging; ketogenic diet; metabolism; propionate; pyruvate; pyruvate dehydrogenase deficiency

DOI:  https://doi.org/10.1016/j.cmet.2024.05.002
Am J Med Genet A. 2024 Jun 06. e63783

A novel homozygous pathogenic missense variant in COX6B1: Further delineation of the phenotype.

E Jennions, M Olsson-Engman, K Visuttijai, Å Wiksell, N Fluriach Dominguez, G Kollberg, A Oldfors, C Hedberg-Oldfors.

  Cytochrome c oxidase (COX) deficiency is a phenotypically diverse group of diseases caused by variants in over 30 genes. Biallelic pathogenic variants in COX6B1 have been described in four patients to date with varying disease manifestations. We describe the clinical features and follow-up of a patient with a novel homozygous pathogenic variant in COX6B1 who presented acutely with severe encephalomyopathy associated with an infection. New findings include ophthalmological evaluation and follow-up of neuroradiological investigations. The novel p.Trp31Arg variant was predicted to be pathogenic in silico, and further functional analyses with biochemical analysis of mitochondrial function showed isolated COX deficiency. Muscle biopsy showed a specific lack of COX6B1 protein together with complex IV deficiency on western blot, enzyme histochemistry, and immuno-histochemistry.

Keywords:  COX deficiency; COX6B1; cavitating leukoencephalopathy

DOI:  https://doi.org/10.1002/ajmg.a.63783
Cureus. 2024 May;16(5): e59669

Late-Onset Leigh Syndrome With Protracted Gastrointestinal Manifestations: A Rare Case Report.

Zain Amar, Helai Hussaini, Meet Popatbhai Kachhadia, Iqra Samreen, Alaa S Mohamed, Hira Nasir.

  Although Leigh syndrome (LS) is a neurodegenerative disorder of infancy, adult-onset LS has also been rarely reported. We report a case of late-onset LS in a 42-year-old female who presented with protracted gastrointestinal manifestations, chronic headaches, ataxia, and loss of consciousness. Brain magnetic resonance imaging (MRI) revealed hyperintensities in the bilateral basal ganglia and brain stem. Serum and cerebrospinal fluid lactate levels were significantly raised. Muscle biopsy showed reduced cytochrome oxidase (COX) activity. She was diagnosed with probable diagnosis of late-onset LS based on her clinical features, radiological findings, biochemical results, and biopsy findings. She responded well to intravenous thiamine, and her symptoms gradually improved.

Keywords:  adult-onset leigh syndrome; late-onset leigh syndrome; leigh syndrome; mitochondrial syndrome; neurodegenrative disease

DOI:  https://doi.org/10.7759/cureus.59669
Dev Cell. 2024 Jun 04. pii: S1534-5807(24)00325-3. [Epub ahead of print]

Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.

Seungyoon B Yu, Haoming Wang, Richard G Sanchez, Natasha M Carlson, Khanh Nguyen, Andrew Zhang, Zachary D Papich, Ahmed A Abushawish, Zachary Whiddon, Weronika Matysik, Jie Zhang, Thomas C Whisenant, Majid Ghassemian, John N Koberstein, Melissa L Stewart, Samuel A Myers, Gulcin Pekkurnaz.

  Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-linked N-acetyl glucosamine (O-GlcNAc) transferase regulates neuronal activity-driven mitochondrial bioenergetics in hippocampal and cortical neurons. We show that neuronal activity upregulates O-GlcNAcylation in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven glucose consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.

Keywords:  ATP synthesis; O-GlcNAc transferase; O-GlcNAcylation; glycosylation; mitochondria; neuronal metabolism; synaptic activity

DOI:  https://doi.org/10.1016/j.devcel.2024.05.008
Neurol Sci. 2024 Jun 01.

An enigmatic pedigree of variable presentations of optic neuropathy due to mitochondrial-ND6 mutation.

Saranya B Gomathy, Animesh Das, Rajesh Kumar Singh, Deepti Vibha, Manjari Tripathi.

DOI: https://doi.org/10.1007/s10072-024-07629-y
Brain Commun. 2024 ;6(3): fcae170

Long non-coding RNA TUG1 is downregulated in Friedreich's ataxia.

Mert Koka, Hui Li, Rumana Akther, Susan Perlman, Darice Wong, Brent L Fogel, David R Lynch, Vijayendran Chandran.

  Friedreich's ataxia is a neurodegenerative disorder caused by reduced frataxin levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia, Friedreich's ataxia lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes TUG1, a long non-coding RNA, as a promising blood-based biomarker for Friedreich's ataxia, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark Friedreich's ataxia symptoms. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from Friedreich's ataxia patients with tissue samples from affected areas in Friedreich's ataxia knockdown mice, tissues usually unattainable from patients-would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of Friedreich's ataxia patients, carriers and controls and 192 tissue data sets from Friedreich's ataxia knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription polymerase chain reaction, and frataxin knockdown was confirmed through enzyme-linked immunosorbent assays. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 Friedreich's ataxia patients and in blood samples from 66 heterozygous carriers and 72 Friedreich's ataxia patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the Friedreich's ataxia knockdown mouse model (one-way ANOVA, P ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R 2 = 0.71 during depletion, R 2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1's downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of Friedreich's ataxia patients compared with controls (Wilcoxon signed-rank test, P < 0.05). Regression analyses revealed a negative correlation between TUG1 fold-change and disease onset (P < 0.0037) and positive correlations with disease duration and functional disability stage score (P < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. This study identifies TUG1 as a potential blood-based biomarker for Friedreich's ataxia, showing consistent expression variance in human and mouse tissues related to disease severity and key Friedreich's ataxia pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for Friedreich's ataxia monitoring and therapeutic development, meriting additional research.

Keywords:  Friedreich's ataxia; TUG1; biomarker; frataxin knockdown; gene expression

DOI:  https://doi.org/10.1093/braincomms/fcae170
Mitochondrion. 2024 Jun 04. pii: S1567-7249(24)00067-9. [Epub ahead of print] 101909

Liver mitochondrial coupling efficiency and its relationship to oxidative capacity and adenine nucleotide translocase content: A comparative study among crocodiles, birds and mammals.

Damien Roussel, Nathan Roussel, Yann Voituron, Benjamin Rey.

  The primary objective of this study was to assess whether adenine nucleotide translocase (ANT) content could be associated with phylogenetic disparities in mitochondrial coupling efficiency, within liver mitochondria obtained from rats, crocodiles, and ducklings. Our measurements included mitochondrial membrane conductance, ANT content, and oxidative phosphorylation fluxes at various steady-state rates. We observed significant variations in liver mitochondrial coupling efficiency across the three species. These variations correlated with interspecific differences in mitochondrial oxidative capacity and, to a lesser extent, the ANT content of liver mitochondria. These findings expand upon previous research by highlighting the pivotal role of oxidative capacity and ANT in modulating mitochondrial efficiency on an interspecific scale.

Keywords:  Adenine nucleotide translocase (ANT); Archosaurs; Liver; Oxidative phosphorylation; Proton leak

DOI:  https://doi.org/10.1016/j.mito.2024.101909
Cell Rep. 2024 Jun 05. pii: S2211-1247(24)00632-6. [Epub ahead of print]43(6): 114304

TRABD modulates mitochondrial homeostasis and tissue integrity.

Caixia Zhou, Zhirong Li, Yawen Li, Yaoyao Li, Wei Wang, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.

  High TRABD expression is associated with tau pathology in patients with Alzheimer's disease; however, the function of TRABD is unknown. Human TRABD encodes a mitochondrial outer-membrane protein. The loss of TRABD resulted in mitochondrial fragmentation, and TRABD overexpression led to mitochondrial clustering and fusion. The C-terminal tail of the TRABD anchored to the mitochondrial outer membrane and the TraB domain could form homocomplexes. Additionally, TRABD forms complexes with MFN2, MIGA2, and PLD6 to facilitate mitochondrial fusion. Flies lacking dTRABD are viable and have normal lifespans. However, aging flies exhibit reduced climbing ability and abnormal mitochondrial morphology in their muscles. The expression of dTRABD is increased in aged flies. dTRABD overexpression leads to neurodegeneration and enhances tau toxicity in fly eyes. The overexpression of dTRABD also increased reactive oxygen species (ROS), ATP production, and protein turnover in the mitochondria. This study suggested that TRABD-induced mitochondrial malfunctions contribute to age-related neurodegeneration.

Keywords:  CP: Cell biology; Drosophila; mitochondria; mitochondria fusion; neurodegeneration

DOI:  https://doi.org/10.1016/j.celrep.2024.114304
Trends Cell Biol. 2024 Jun 06. pii: S0962-8924(24)00111-9. [Epub ahead of print]

Lysosomal control of the cGAS-STING signaling.

Yinfeng Xu, Wei Wan.

  The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in combating pathogen infection. However, its aberrant activation is involved in several human disorders. Lysosomes are emerging as key negative regulators of cGAS-STING signaling. Here, we discuss the lysosomal control of cGAS-STING signaling and its implication in human disorders.

Keywords:  STING; autophagy; cGAS; human disorders; innate immunity; lysosome

DOI:  https://doi.org/10.1016/j.tcb.2024.05.004
Life Sci Alliance. 2024 Aug;pii: e202402828. [Epub ahead of print]7(8):

Mitochondrial lipidomes are tissue specific - low cholesterol contents relate to UCP1 activity.

Sarah Brunner, Marcus Höring, Gerhard Liebisch, Sabine Schweizer, Josef Scheiber, Piero Giansanti, Maria Hidrobo, Sven Hermeling, Josef Oeckl, Natalia Prudente de Mello, Fabiana Perocchi, Claudine Seeliger, Akim Strohmeyer, Martin Klingenspor, Johannes Plagge, Bernhard Küster, Ralph Burkhardt, Klaus-Peter Janssen, Josef Ecker.

Lipid composition is conserved within sub-cellular compartments to maintain cell function. Lipidomic analyses of liver, muscle, white and brown adipose tissue (BAT) mitochondria revealed substantial differences in their glycerophospholipid (GPL) and free cholesterol (FC) contents. The GPL to FC ratio was 50-fold higher in brown than white adipose tissue mitochondria. Their purity was verified by comparison of proteomes with ER and mitochondria-associated membranes. A lipid signature containing PC and FC, calculated from the lipidomic profiles, allowed differentiation of mitochondria from BAT of mice housed at different temperatures. Elevating FC in BAT mitochondria prevented uncoupling protein (UCP) 1 function, whereas increasing GPL boosted it. Similarly, STARD3 overexpression facilitating mitochondrial FC import inhibited UCP1 function in primary brown adipocytes, whereas a knockdown promoted it. We conclude that the mitochondrial GPL/FC ratio is key for BAT function and propose that targeting it might be a promising strategy to promote UCP1 activity.

DOI: https://doi.org/10.26508/lsa.202402828
Cell Biosci. 2024 Jun 08. 14(1): 76

Mitochondrial mechanisms in the pathogenesis of chronic inflammatory musculoskeletal disorders.

Kailun Wu, Ju-Sheng Shieh, Ling Qin, Jiong Jiong Guo.

  Chronic inflammatory musculoskeletal disorders characterized by prolonged muscle inflammation, resulting in enduring pain and diminished functionality, pose significant challenges for the patients. Emerging scientific evidence points to mitochondrial malfunction as a pivotal factor contributing to these ailments. Mitochondria play a critical role in powering skeletal muscle activity, but in the context of persistent inflammation, disruptions in their quantity, configuration, and performance have been well-documented. Various disturbances, encompassing alterations in mitochondrial dynamics (such as fission and fusion), calcium regulation, oxidative stress, biogenesis, and the process of mitophagy, are believed to play a central role in the progression of these disorders. Additionally, unfolded protein responses and the accumulation of fatty acids within muscle cells may adversely affect the internal milieu, impairing the equilibrium of mitochondrial functioning. The structural discrepancies between different mitochondrial subsets namely, intramyofibrillar and subsarcolemmal mitochondria likely impact their metabolic capabilities and susceptibility to inflammatory influences. The release of signals from damaged mitochondria is known to incite inflammatory responses. Intriguingly, migrasomes and extracellular vesicles serve as vehicles for intercellular transfer of mitochondria, aiding in the removal of impaired mitochondria and regulation of inflammation. Viral infections have been implicated in inducing stress on mitochondria. Prolonged dysfunction of these vital organelles sustains oxidative harm, metabolic irregularities, and heightened cytokine release, impeding the body's ability to repair tissues. This review provides a comprehensive analysis of advancements in understanding changes in the intracellular environment, mitochondrial architecture and distribution, biogenesis, dynamics, autophagy, oxidative stress, cytokines associated with mitochondria, vesicular structures, and associated membranes in the context of chronic inflammatory musculoskeletal disorders. Strategies targeting key elements regulating mitochondrial quality exhibit promise in the restoration of mitochondrial function, alleviation of inflammation, and enhancement of overall outcomes.

Keywords:  Chronic inflammatory musculoskeletal disorders; Extracellular vesicles; Mitochondrial calcium overload; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1186/s13578-024-01259-9
Int J Cardiol. 2024 Jun 04. pii: S0167-5273(24)00849-0. [Epub ahead of print] 132227

Safety and efficacy of platelet-derived mitochondrial transplantation in ischaemic heart disease.

Fatemeh Baharvand, Mehryar Habibi Roudkenar, Zahra Pourmohammadi-Bejarpasi, Nima Najafi Ghalehlou, Alireza Feizkhah, Somaye Bashiri Aliabadi, Arsalan Salari, Amaneh Mohammadi Roushandeh.

  BACKGROUND: Acute ST-elevation myocardial infarction (STEMI) remains a globally significant health challenge in spite of improvement in management strategy. Being aware that mitochondrial dysfunction plays a crucial role in ischaemia-reperfusion injury (IRI) modulation, empirical evidence suggests functional mitochondrial transplantation strikes as a reliable therapeutic approach for patients with acute myocardial infarction.METHODS AND RESULTS: We conducted a prospective, triple-blinded, parallel-group, blocked randomised clinical trial to investigate the therapeutic effects and clinical outcomes of platelet-derived mitochondrial transplantation in 30 patients with acute STEMI, such that the 15 subjects in the control group were given standard of care treatment, whereas the subjects in the intervention group received autologous platelet-derived mitochondria through the intracoronary injection. We observed that within 40 days, the intervention group had a slightly greater improvement in the left ventricular ejection fraction (LVEF) compared to the control group and experienced a significant enhancement in the exercise capacity (p < 0.001). Moreover, major adverse cardiac events (MACE), arrhythmia, fever, and tachycardia were compared between the groups and lack of significant difference marks the safety of mitochondrial transplantation (p > 0.05). Furthermore, the two groups were not significantly distinct as regards the average length of stay for a hospitalisation (p > 0.05).
CONCLUSION: We suggest platelet-derived mitochondrial transplantation appears as a beneficial and highly promising therapeutic option for patients of ischaemic heart disease (IHD); however, we are aware that further in-depth studies with larger sample sizes along with longer follow-up periods are necessary for validating the clinical implications of our findings.

Keywords:  Acute ST-elevation myocardial infarction; Acute myocardial infarction; Ischaemia-reperfusion injury; Mitochondrial transplantation

DOI:  https://doi.org/10.1016/j.ijcard.2024.132227
Nat Commun. 2024 Jun 03. 15(1): 4700

Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.

Shashank Dadsena, Rodrigo Cuevas Arenas, Gonçalo Vieira, Susanne Brodesser, Manuel N Melo, Ana J García-Sáez.

BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions. We then demonstrate that unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria and cellular systems, which is further supported by molecular dynamics simulations. Accordingly, the fatty acid desaturase FADS2 not only enhances apoptosis sensitivity, but also the activation of the cGAS/STING pathway downstream mtDNA release. The correlation of FADS2 levels with the sensitization to apoptosis of different lung and kidney cancer cell lines by co-treatment with unsaturated fatty acids supports the relevance of our findings. Altogether, our work provides an insight on how local lipid environment affects BAX and BAK function during apoptosis.

DOI: https://doi.org/10.1038/s41467-024-49067-6
Cell Metab. 2024 May 25. pii: S1550-4131(24)00182-7. [Epub ahead of print]

Personalized metabolic whole-body models for newborns and infants predict growth and biomarkers of inherited metabolic diseases.

Elaine Zaunseder, Ulrike Mütze, Jürgen G Okun, Georg F Hoffmann, Stefan Kölker, Vincent Heuveline, Ines Thiele.

  Comprehensive whole-body models (WBMs) accounting for organ-specific dynamics have been developed to simulate adult metabolism, but such models do not exist for infants. Here, we present a resource of 360 organ-resolved, sex-specific models of newborn and infant metabolism (infant-WBMs) spanning the first 180 days of life. These infant-WBMs were parameterized to represent the distinct metabolic characteristics of newborns and infants, including nutrition, energy requirements, and thermoregulation. We demonstrate that the predicted infant growth was consistent with the recommendation by the World Health Organization. We assessed the infant-WBMs' reliability and capabilities for personalization by simulating 10,000 newborns based on their blood metabolome and birth weight. Furthermore, the infant-WBMs accurately predicted changes in known biomarkers over time and metabolic responses to treatment strategies for inherited metabolic diseases. The infant-WBM resource holds promise for personalized medicine, as the infant-WBMs could be a first step to digital metabolic twins for newborn and infant metabolism.

Keywords:  constraint-based metabolic modeling; digital metabolic twins; infant metabolism; inherited metabolic diseases; metabolism; metabolomics; newborn screening

DOI:  https://doi.org/10.1016/j.cmet.2024.05.006
Pediatr Res. 2024 Jun 06.

Aberrant PGC-1α signaling in a lamb model of persistent pulmonary hypertension of the newborn.

Emily A Mooers, Hollis M Johnson, Teresa Michalkiewicz, Ujala Rana, Chintamani Joshi, Adeleye J Afolayan, Ru-Jeng Teng, Girija G Konduri.

BACKGROUND: Persistent Pulmonary Hypertension of the Newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR), resulting in hypoxemia. Impaired angiogenesis contributes to high PVR. Pulmonary artery endothelial cells (PAECs) in PPHN exhibit decreased mitochondrial respiration and angiogenesis. We hypothesize that Peroxisome Proliferator-Activated Receptor Gamma Co-Activator-1α (PGC-1α) downregulation leads to reduced mitochondrial function and angiogenesis in PPHN.METHODS: Studies were performed in PAECs isolated from fetal lambs with PPHN induced by ductus arteriosus constriction, with gestation-matched controls and in normal human umbilical vein endothelial cells (HUVECs). PGC-1α was knocked downed in control lamb PAECs and HUVECs and overexpressed in PPHN PAECs to investigate the effects on mitochondrial function and angiogenesis.
RESULTS: PPHN PAECs had decreased PGC-1α expression compared to controls. PGC-1α knockdown in HUVECs led to reduced Nuclear Respiratory Factor-1 (NRF-1), Transcription Factor-A of Mitochondria (TFAM), and mitochondrial electron transport chain (ETC) complexes expression. PGC-1α knockdown in control PAECs led to decreased in vitro capillary tube formation, cell migration, and proliferation. PGC-1α upregulation in PPHN PAECs led to increased ETC complexes expression and improved tube formation, cell migration, and proliferation.
CONCLUSION: PGC-1α downregulation contributes to reduced mitochondrial oxidative phosphorylation through control of the ETC complexes, thereby affecting angiogenesis in PPHN.
IMPACT: Reveals a novel mechanism for angiogenesis dysfunction in persistent pulmonary hypertension of the newborn (PPHN). Identifies a key mitochondrial transcription factor, Peroxisome Proliferator-Activated Receptor Gamma Co-Activator-1α (PGC-1α), as contributing to the altered adaptation and impaired angiogenesis function that characterizes PPHN through its regulation of mitochondrial function and oxidative phosphorylation. May provide translational significance as this mechanism offers a new therapeutic target in PPHN, and efforts to restore PGC-1α expression may improve postnatal transition in PPHN.

DOI: https://doi.org/10.1038/s41390-024-03223-2