bims-mitmed 2023-05-28 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023‒05‒28
thirty-two papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico

A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.
Strand-selective base editing of human mitochondrial DNA using mitoBEs.
Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease.
Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases.
CRISPR-free, strand-selective mitochondrial DNA base editing using a nickase.
Leigh syndrome mimicking neuromyelitis optica spectrum disorder (NMOSD).
Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice.
Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials.
Mitochondria in Human Fertility and Infertility.
Mitochondria Have Made a Long Evolutionary Path from Ancient Bacteria Immigrants within Eukaryotic Cells to Essential Cellular Hosts and Key Players in Human Health and Disease.
Mitochondrial Transfer as a Novel Therapeutic Approach in Disease Diagnosis and Treatment.
Mitochondrial respiratory complex I proteostasis: The role of a subunit turnover rate.
Mitochondrial transplantation as a possible therapeutic option for sarcopenia.
Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes.
The role of the PLA2G6 gene in neurodegenerative diseases.
Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
Glycolytically impaired Drosophila glial cells fuel neural metabolism via β-oxidation.
A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia.
Identification of Novel Biomarkers of Spinal Muscular Atrophy and Therapeutic Response by Proteomic and Metabolomic Profiling of Human Biological Fluid Samples.
Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration.
COX17 restricts renal fibrosis development by maintaining mitochondrial copper homeostasis and restoring complex IV activity.
Exercise metabolism and adaptation in skeletal muscle.
Mitochondrial Transplantation Preserves Myocardial Function and Viability in Pediatric and Neonatal Donation After Circulatory Death Pig Hearts.
Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers.
PGC-1α Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response.
Mother's milk helps baby mouse hearts to develop.
Mitochondrial dysfunction-targeting therapeutics of natural products in Parkinson's disease.
A mitochondrial-targeted antioxidant (MitoQ) improves motor coordination and reduces Purkinje cell death in a mouse model of ARSACS.
AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration.
Redefining the role of AMPK in autophagy and the energy stress response.
Metabolic Priming as a Tool in Redox and Mitochondrial Theragnostics.
Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction.

EMBO Mol Med. 2023 May 24. e16951

A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.

Nneka Southwell, Guido Primiano, Viraj Nadkarni, Nabeel Attarwala, Emelie Beattie, Dawson Miller, Sumaitaah Alam, Irene Liparulo, Yevgeniya I Shurubor, Maria Lucia Valentino, Valerio Carelli, Serenella Servidei, Steven S Gross, Giovanni Manfredi, Qiuying Chen, Marilena D'Aurelio.

  Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.

Keywords:  amino acid metabolism; glucocorticoids; leptin; mitochondrial myopathy; muscle wasting

DOI:  https://doi.org/10.15252/emmm.202216951
Nat Biotechnol. 2023 May 22.

Strand-selective base editing of human mitochondrial DNA using mitoBEs.

Zongyi Yi, Xiaoxue Zhang, Wei Tang, Ying Yu, Xiaoxu Wei, Xue Zhang, Wensheng Wei.

A number of mitochondrial diseases in humans are caused by point mutations that could be corrected by base editors, but delivery of CRISPR guide RNAs into the mitochondria is difficult. In this study, we present mitochondrial DNA base editors (mitoBEs), which combine a transcription activator-like effector (TALE)-fused nickase and a deaminase for precise base editing in mitochondrial DNA. Combining mitochondria-localized, programmable TALE binding proteins with the nickase MutH or Nt.BspD6I(C) and either the single-stranded DNA-specific adenine deaminase TadA8e or the cytosine deaminase ABOBEC1 and UGI, we achieve A-to-G or C-to-T base editing with up to 77% efficiency and high specificity. We find that mitoBEs are DNA strand-selective mitochondrial base editors, with editing results more likely to be retained on the nonnicked DNA strand. Furthermore, we correct pathogenic mitochondrial DNA mutations in patient-derived cells by delivering mitoBEs encoded in circular RNAs. mitoBEs offer a precise, efficient DNA editing tool with broad applicability for therapy in mitochondrial genetic diseases.

DOI: https://doi.org/10.1038/s41587-023-01791-y
Int J Mol Sci. 2023 May 09. pii: 8505. [Epub ahead of print]24(10):

Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease.

Kaela O'Connor, Sally Spendiff, Hanns Lochmüller, Rita Horvath.

  Congenital myasthenic syndromes (CMS) are a group of rare, neuromuscular disorders that usually present in childhood or infancy. While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission. Recently, two mitochondrial genes-SLC25A1 and TEFM-have been reported in patients with suspected CMS, prompting a discussion about the role of mitochondria at the neuromuscular junction (NMJ). Mitochondrial disease and CMS can present with similar symptoms, and potentially one in four patients with mitochondrial myopathy exhibit NMJ defects. This review highlights research indicating the prominent roles of mitochondria at both the pre- and postsynapse, demonstrating the potential for mitochondrial involvement in neuromuscular transmission defects. We propose the establishment of a novel subcategorization for CMS-mitochondrial CMS, due to unifying clinical features and the potential for mitochondrial defects to impede transmission at the pre- and postsynapse. Finally, we highlight the potential of targeting the neuromuscular transmission in mitochondrial disease to improve patient outcomes.

Keywords:  SLC25A1; TEFM; congenital myasthenic syndrome; mitochondria; mitochondrial disease; neuromuscular; neuromuscular junction

DOI:  https://doi.org/10.3390/ijms24108505
J Transl Med. 2023 May 25. 21(1): 347

Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases.

Mingchu Sun, Wenhua Jiang, Nan Mu, Zihui Zhang, Lu Yu, Heng Ma.

  Cardiovascular disease (CVD) is the leading cause of noncommunicable disease-related death worldwide, and effective therapeutic strategies against CVD are urgently needed. Mitochondria dysfunction involves in the onset and development of CVD. Nowadays, mitochondrial transplantation, an alternative treatment aimed at increasing mitochondrial number and improving mitochondrial function, has been emerged with great therapeutic potential. Substantial evidence indicates that mitochondrial transplantation improves cardiac function and outcomes in patients with CVD. Therefore, mitochondrial transplantation has profound implications in the prevention and treatment of CVD. Here, we review the mitochondrial abnormalities that occur in CVD and summarize the therapeutic strategies of mitochondrial transplantation for CVD.

Keywords:  Cardiovascular diseases; Ischemia reperfusion injury; Mitochondrial dysfunction; Mitochondrial transplantation; Therapy

DOI:  https://doi.org/10.1186/s12967-023-04203-6
Nat Biotechnol. 2023 May 22.

CRISPR-free, strand-selective mitochondrial DNA base editing using a nickase.

DOI: https://doi.org/10.1038/s41587-023-01820-w
Mult Scler. 2023 May 25. 13524585231172950

Leigh syndrome mimicking neuromyelitis optica spectrum disorder (NMOSD).

Nee Na Kim, Omar Abdel-Mannan, James Davidson, Pascale Du Pre, Rachel Kneen, Kshitij Mankad, Yael Hacohen.

  We report two children with molecularly confirmed mitochondrial disease mimicking Neuromyelitis Optica Spectrum Disorder (NMOSD). The first patient presented at the age of 15 months with acute deterioration following a pyrexial illness with clinical features localising to the brainstem and spinal cord. The second patient presented at 5 years with acute bilateral visual loss. In both cases, MOG and AQP4 antibodies were negative. Both patients died within a year of symptoms onset from respiratory failure. Arriving at an early genetic diagnosis is important for redirection of care and avoiding potentially harmful immunosuppressant therapies.

Keywords:  Neuromyelitis optica spectrum disorder; acquired demyelinating syndromes; mitochondrial diseases; neurogenetics

DOI:  https://doi.org/10.1177/13524585231172950
Antioxidants (Basel). 2023 Apr 26. pii: 1001. [Epub ahead of print]12(5):

Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice.

Biyi Chen, Nastaran Daneshgar, Hsiang-Chun Lee, Long-Sheng Song, Dao-Fu Dai.

  Mitochondrial oxidative stress has been implicated in aging and several cardiovascular diseases, including heart failure and cardiomyopathy, ventricular tachycardia, and atrial fibrillation. The role of mitochondrial oxidative stress in bradyarrhythmia is less clear. Mice with a germline deletion of Ndufs4 subunit respiratory complex I develop severe mitochondrial encephalomyopathy resembling Leigh Syndrome (LS). Several types of cardiac bradyarrhythmia are present in LS mice, including a frequent sinus node dysfunction and episodic atrioventricular (AV) block. Treatment with the mitochondrial antioxidant Mitotempo or mitochondrial protective peptide SS31 significantly ameliorated the bradyarrhythmia and extended the lifespan of LS mice. Using an ex vivo Langendorff perfused heart with live confocal imaging of mitochondrial and total cellular reactive oxygen species (ROS), we showed increased ROS in the LS heart, which was potentiated by ischemia-reperfusion. A simultaneous ECG recording showed a sinus node dysfunction and AV block concurrent with the severity of the oxidative stress. Treatment with Mitotempo abolished ROS and restored the sinus rhythm. Our study reveals robust evidence of the direct mechanistic roles of mitochondrial and total ROS in bradyarrhythmia in the setting of LS mitochondrial cardiomyopathy. Our study also supports the potential clinical application of mitochondrial-targeted antioxidants or SS31 for the treatment of LS patients.

Keywords:  Leigh Syndrome; arrhythmia; bradycardia; cardiomyopathy; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/antiox12051001
Biomedicines. 2023 Apr 27. pii: 1293. [Epub ahead of print]11(5):

Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials.

Jessica Tiberi, Marco Segatto, Maria Teresa Fiorenza, Piergiorgio La Rosa.

  Friedreich's ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of FXN gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signalling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signalling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, we overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies.

Keywords:  FRDA; Friedreich’s ataxia; NRF2; ROS; antioxidants; oxidative stress

DOI:  https://doi.org/10.3390/biomedicines11051293
Int J Mol Sci. 2023 May 18. pii: 8950. [Epub ahead of print]24(10):

Mitochondria in Human Fertility and Infertility.

Jan Tesarik, Raquel Mendoza-Tesarik.

  In human spermatozoa and oocytes (and their surrounding granulosa cells), mitochondria carry out important functions relating to human fertility and infertility. Sperm mitochondria are not transmitted to the future embryo, but are closely related to the generation of energy needed for sperm movement, capacitation, and acrosome reactions, as well as for sperm-oocyte fusion. On the other hand, oocyte mitochondria produce energy required for oocyte meiotic division and their abnormalities can thus cause oocyte and embryo aneuploidy. In addition, they play a role in oocyte calcium metabolism and in essential epigenetic events during the oocyte-to-embryo transition. They are transmitted to the future embryos and may thus cause hereditary diseases in the offspring. Due to the long life span of the female germ cells, the accumulation of mitochondrial DNA abnormalities often causes ovarian aging. Mitochondrial substitution therapy is the only way of dealing with these issues nowadays. New therapies based on mitochondrial DNA editing are under investigation.

Keywords:  fertility; infertility; mitochondria; mitochondrial therapy; oocyte; sperm

DOI:  https://doi.org/10.3390/ijms24108950
Curr Issues Mol Biol. 2023 May 19. 45(5): 4451-4479

Mitochondria Have Made a Long Evolutionary Path from Ancient Bacteria Immigrants within Eukaryotic Cells to Essential Cellular Hosts and Key Players in Human Health and Disease.

Anna Atlante, Daniela Valenti.

  Mitochondria have made a long evolutionary path from ancient bacteria immigrants within the eukaryotic cell to become key players for the cell, assuming crucial multitasking skills critical for human health and disease. Traditionally identified as the powerhouses of eukaryotic cells due to their central role in energy metabolism, these chemiosmotic machines that synthesize ATP are known as the only maternally inherited organelles with their own genome, where mutations can cause diseases, opening up the field of mitochondrial medicine. More recently, the omics era has highlighted mitochondria as biosynthetic and signaling organelles influencing the behaviors of cells and organisms, making mitochondria the most studied organelles in the biomedical sciences. In this review, we will especially focus on certain 'novelties' in mitochondrial biology "left in the shadows" because, although they have been discovered for some time, they are still not taken with due consideration. We will focus on certain particularities of these organelles, for example, those relating to their metabolism and energy efficiency. In particular, some of their functions that reflect the type of cell in which they reside will be critically discussed, for example, the role of some carriers that are strictly functional to the typical metabolism of the cell or to the tissue specialization. Furthermore, some diseases in whose pathogenesis, surprisingly, mitochondria are involved will be mentioned.

Keywords:  ancient bacteria; cardiolipin; cell death; mitochondria; mitochondria-related disorders; mitochondrial dysfunction; mitochondrial energy metabolism

DOI:  https://doi.org/10.3390/cimb45050283
Int J Mol Sci. 2023 May 16. pii: 8848. [Epub ahead of print]24(10):

Mitochondrial Transfer as a Novel Therapeutic Approach in Disease Diagnosis and Treatment.

Vicente Javier Clemente-Suárez, Alexandra Martín-Rodríguez, Rodrigo Yáñez-Sepúlveda, José Francisco Tornero-Aguilera.

  Mitochondrial dysfunction is a hallmark of numerous diseases, including neurodegenerative disorders, metabolic disorders, and cancer. Mitochondrial transfer, the transfer of mitochondria from one cell to another, has recently emerged as a potential therapeutic approach for restoring mitochondrial function in diseased cells. In this review, we summarize the current understanding of mitochondrial transfer, including its mechanisms, potential therapeutic applications, and impact on cell death pathways. We also discuss the future directions and challenges in the field of mitochondrial transfer as a novel therapeutic approach in disease diagnosis and treatment.

Keywords:  cancer; cell death; disease diagnosis; disease treatment; metabolic disorders; mitochondrial transfer; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms24108848
Plant Cell. 2023 May 23. pii: koad149. [Epub ahead of print]

Mitochondrial respiratory complex I proteostasis: The role of a subunit turnover rate.

Lucas Frungillo.

DOI: https://doi.org/10.1093/plcell/koad149
J Mol Med (Berl). 2023 May 20.

Mitochondrial transplantation as a possible therapeutic option for sarcopenia.

Ibrahim Turkel, Berkay Ozerklig, Merve Yılmaz, Oner Ulger, Gokhan Burcin Kubat, Meltem Tuncer.

  With advancing age, the skeletal muscle phenotype is characterized by a progressive loss of mass, strength, and quality. This phenomenon, known as sarcopenia, has a negative impact on quality of life and increases the risk of morbidity and mortality in older adults. Accumulating evidence suggests that damaged and dysfunctional mitochondria play a critical role in the pathogenesis of sarcopenia. Lifestyle modifications, such as physical activity, exercise, and nutrition, as well as medical interventions with therapeutic agents, are effective in the management of sarcopenia and offer solutions to maintain and improve skeletal muscle health. Although a great deal of effort has been devoted to the identification of the best treatment option, these strategies are not sufficient to overcome sarcopenia. Recently, it has been reported that mitochondrial transplantation may be a possible therapeutic approach for the treatment of mitochondria-related pathological conditions such as ischemia, liver toxicity, kidney injury, cancer, and non-alcoholic fatty liver disease. Given the role of mitochondria in the function and metabolism of skeletal muscle, mitochondrial transplantation may be a possible option for the treatment of sarcopenia. In this review, we summarize the definition and characteristics of sarcopenia and molecular mechanisms associated with mitochondria that are known to contribute to sarcopenia. We also discuss mitochondrial transplantation as a possible option. Despite the progress made in the field of mitochondrial transplantation, further studies are needed to elucidate the role of mitochondrial transplantation in sarcopenia. KEY MESSAGES: Sarcopenia is the progressive loss of skeletal muscle mass, strength, and quality. Although the specific mechanisms that lead to sarcopenia are not fully understood, mitochondria have been identified as a key factor in the development of sarcopenia. Damaged and dysfunctional mitochondria initiate various cellular mediators and signaling pathways, which largely contribute to the age-related loss of skeletal muscle mass and strength. Mitochondrial transplantation has been reported to be a possible option for the treatment/prevention of several diseases. Mitochondrial transplantation may be a possible therapeutic option for improving skeletal muscle health and treating sarcopenia. Mitochondrial transplantation as a possible treatment option for sarcopenia.

Keywords:  Mitochondrial dysfunction; Mitochondrial transplantation; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1007/s00109-023-02326-3
Nat Cell Biol. 2023 May 22.

Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes.

Tingting Fu, Wanping Sun, Jiachen Xue, Zheng Zhou, Wen Wang, Qiqi Guo, Xinyi Chen, Danxia Zhou, Zhisheng Xu, Lin Liu, Liwei Xiao, Yan Mao, Likun Yang, Yujing Yin, Xue-Na Zhang, Qiangyou Wan, Bin Lu, Yuncong Chen, Min-Sheng Zhu, Philipp E Scherer, Lei Fang, Hai-Long Piao, Mengle Shao, Zhenji Gan.

Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Thermogenic stimulation selectively promotes mitochondrial proteostasis in mature white adipocytes via the mitochondrial protease LONP1. Disruption of LONP1-dependent proteolysis substantially impairs cold- or β3 adrenergic agonist-induced white-to-beige identity switching of mature adipocytes. Mechanistically, LONP1 selectively degrades succinate dehydrogenase complex iron sulfur subunit B and ensures adequate intracellular succinate levels. This alters the histone methylation status on thermogenic genes and thereby enables adipocyte cell fate programming. Finally, augmented LONP1 expression raises succinate levels and corrects ageing-related impairments in white-to-beige adipocyte conversion and adipocyte thermogenic capacity. Together, these findings reveal that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and directs cell identity conversion during adipocyte thermogenic remodelling.

DOI: https://doi.org/10.1038/s41556-023-01155-3
Ageing Res Rev. 2023 May 24. pii: S1568-1637(23)00116-2. [Epub ahead of print] 101957

The role of the PLA2G6 gene in neurodegenerative diseases.

Xinyue Deng, Lamei Yuan, Joseph Jankovic, Hao Deng.

  PLA2G6-associated neurodegeneration (PLAN) represents a continuum of clinically and genetically heterogeneous neurodegenerative disorders with overlapping features. Usually, it encompasses three autosomal recessive diseases, including infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (NBIA) 2A, atypical neuronal dystrophy with childhood-onset or NBIA2B, and adult-onset dystonia-parkinsonism form named PARK14, and possibly a certain subtype of hereditary spastic paraplegia. PLAN is caused by variants in the phospholipase A2 group VI gene (PLA2G6), which encodes an enzyme involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation. In this review, we discuss PLA2G6 gene structure and protein, functional findings, genetic deficiency models, various PLAN disease phenotypes, and study strategies in the future. Our primary aim is to provide an overview of genotype-phenotype correlations of PLAN subtypes and speculate on the role of PLA2G6 in potential mechanisms underlying these conditions.

Keywords:  Genetics; Neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation; Neurodegenerative disorders; PLA2G6 gene; Parkinsonism

DOI:  https://doi.org/10.1016/j.arr.2023.101957
Nat Commun. 2023 May 24. 14(1): 2847

Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.

Zoë P Van Acker, Anika Perdok, Ruben Hellemans, Katherine North, Inge Vorsters, Cedric Cappel, Jonas Dehairs, Johannes V Swinnen, Ragna Sannerud, Marine Bretou, Markus Damme, Wim Annaert.

Phospholipase D3 (PLD3) polymorphisms are linked to late-onset Alzheimer's disease (LOAD). Being a lysosomal 5'-3' exonuclease, its neuronal substrates remained unknown as well as how a defective lysosomal nucleotide catabolism connects to AD-proteinopathy. We identified mitochondrial DNA (mtDNA) as a major physiological substrate and show its manifest build-up in lysosomes of PLD3-defective cells. mtDNA accretion creates a degradative (proteolytic) bottleneck that presents at the ultrastructural level as a marked abundance of multilamellar bodies, often containing mitochondrial remnants, which correlates with increased PINK1-dependent mitophagy. Lysosomal leakage of mtDNA to the cytosol activates cGAS-STING signaling that upregulates autophagy and induces amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation. STING inhibition largely normalizes APP-CTF levels, whereas an APP knockout in PLD3-deficient backgrounds lowers STING activation and normalizes cholesterol biosynthesis. Collectively, we demonstrate molecular cross-talks through feedforward loops between lysosomal nucleotide turnover, cGAS-STING and APP metabolism that, when dysregulated, result in neuronal endolysosomal demise as observed in LOAD.

DOI: https://doi.org/10.1038/s41467-023-38501-w
Nat Commun. 2023 May 24. 14(1): 2996

Glycolytically impaired Drosophila glial cells fuel neural metabolism via β-oxidation.

Ellen McMullen, Helen Hertenstein, Katrin Strassburger, Leon Deharde, Marko Brankatschk, Stefanie Schirmeier.

Neuronal function is highly energy demanding and thus requires efficient and constant metabolite delivery by glia. Drosophila glia are highly glycolytic and provide lactate to fuel neuronal metabolism. Flies are able to survive for several weeks in the absence of glial glycolysis. Here, we study how Drosophila glial cells maintain sufficient nutrient supply to neurons under conditions of impaired glycolysis. We show that glycolytically impaired glia rely on mitochondrial fatty acid breakdown and ketone body production to nourish neurons, suggesting that ketone bodies serve as an alternate neuronal fuel to prevent neurodegeneration. We show that in times of long-term starvation, glial degradation of absorbed fatty acids is essential to ensure survival of the fly. Further, we show that Drosophila glial cells act as a metabolic sensor and can induce mobilization of peripheral lipid stores to preserve brain metabolic homeostasis. Our study gives evidence of the importance of glial fatty acid degradation for brain function, and survival, under adverse conditions in Drosophila.

DOI: https://doi.org/10.1038/s41467-023-38813-x
Cerebellum. 2023 May 23.

A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia.

S H Subramony, D L Lynch.

  The exciting news about the US FDA approval of omaveloxolone as the first-ever drug to be approved for an inherited ataxia is welcome news for patients and families that deal with this devastating disease as well as for health care providers and investigators with an interest in this and other rare diseases. This event is the culmination of long and fruitful collaboration between patients, their families, clinicians, laboratory researchers, patient advocacy organizations, industry, and regulatory agencies. The process has generated intense discussion about outcome measures, biomarkers, trial design, and the nature of approval process for such diseases. It also has brought hope and enthusiasm for increasingly better therapies for genetic diseases in general.

Keywords:  Clinical trial; Drug approval; Friedreich ataxia; Nrf 2; Omaveloxolone

DOI:  https://doi.org/10.1007/s12311-023-01568-8
Biomedicines. 2023 Apr 23. pii: 1254. [Epub ahead of print]11(5):

Identification of Novel Biomarkers of Spinal Muscular Atrophy and Therapeutic Response by Proteomic and Metabolomic Profiling of Human Biological Fluid Samples.

Megi Meneri, Elena Abati, Delia Gagliardi, Irene Faravelli, Valeria Parente, Antonia Ratti, Federico Verde, Nicola Ticozzi, Giacomo P Comi, Linda Ottoboni, Stefania Corti.

  Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations or deletions in SMN1 that lead to progressive death of alpha motor neurons, ultimately leading to severe muscle weakness and atrophy, as well as premature death in the absence of treatment. Recent approval of SMN-increasing medications as SMA therapy has altered the natural course of the disease. Thus, accurate biomarkers are needed to predict SMA severity, prognosis, drug response, and overall treatment efficacy. This article reviews novel non-targeted omics strategies that could become useful clinical tools for patients with SMA. Proteomics and metabolomics can provide insights into molecular events underlying disease progression and treatment response. High-throughput omics data have shown that untreated SMA patients have different profiles than controls. In addition, patients who clinically improved after treatment have a different profile than those who did not. These results provide a glimpse on potential markers that could assist in identifying therapy responders, in tracing the course of the disease, and in predicting its outcome. These studies have been restricted by the limited number of patients, but the approaches are feasible and can unravel severity-specific neuro-proteomic and metabolic SMA signatures.

Keywords:  antisense oligonucleotide; cerebrospinal fluid; metabolome; nusinersen; proteome; spinal muscular atrophy

DOI:  https://doi.org/10.3390/biomedicines11051254
Int J Mol Sci. 2023 May 15. pii: 8763. [Epub ahead of print]24(10):

Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration.

Raji Rajesh Lenin, Yi Hui Koh, Zheting Zhang, Yan Zhuang Yeo, Bhav Harshad Parikh, Ivan Seah, Wendy Wong, Xinyi Su.

  Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics.

Keywords:  age-related macular degeneration; aging; autophagy; clinical trials; mitochondrial dysfunction; retinal pigment epithelium

DOI:  https://doi.org/10.3390/ijms24108763
Acta Pharmacol Sin. 2023 May 22.

COX17 restricts renal fibrosis development by maintaining mitochondrial copper homeostasis and restoring complex IV activity.

Sai-Ya Zhu, Wen-Qian Zhou, Yang-Yang Niu, Chao Zheng, Xi Liu, Ying-Ying Zhang, Chen Yu.

  Renal fibrosis relies on multiple proteins and cofactors in its gradual development. Copper is a cofactor of many enzymes involved in renal microenvironment homeostasis. We previously reported that intracellular copper imbalance occurred during renal fibrosis development and was correlated with fibrosis intensity. In this study, we investigated the molecular mechanisms of how copper affected renal fibrosis development. Unilateral ureteral obstruction (UUO) mice were used for in vivo study; rat renal tubular epithelial cells (NRK-52E) treated with TGF-β1 were adapted as an in vitro fibrotic model. We revealed that the accumulation of copper in mitochondria, rather than cytosol, was responsible for mitochondrial dysfunction, cell apoptosis and renal fibrosis in both in vivo and in vitro fibrotic models. Furthermore, we showed that mitochondrial copper overload directly disrupted the activity of respiratory chain complex IV (cytochrome c oxidase), but not complex I, II and III, which hampered respiratory chain and disrupted mitochondrial functions, eventually leading to fibrosis development. Meanwhile, we showed that COX17, the copper chaperone protein, was significantly upregulated in the mitochondria of fibrotic kidneys and NRK-52E cells. Knockdown of COX17 aggravated mitochondrial copper accumulation, inhibited complex IV activity, augmented mitochondrial dysfunction and led to cell apoptosis and renal fibrosis, whereas overexpression of COX17 could discharge copper from mitochondria and protect mitochondrial function, alleviating renal fibrosis. In conclusion, copper accumulation in mitochondria blocks complex IV activity and induces mitochondrial dysfunction. COX17 plays a pivotal role in maintaining mitochondrial copper homeostasis, restoring complex IV activity, and ameliorating renal fibrosis.

Keywords:  COX17; NRK-52E cells; copper; cytochrome c oxidase; mitochondria; renal fibrosis

DOI:  https://doi.org/10.1038/s41401-023-01098-3
Nat Rev Mol Cell Biol. 2023 May 24.

Exercise metabolism and adaptation in skeletal muscle.

Jonathon A B Smith, Kevin A Murach, Kenneth A Dyar, Juleen R Zierath.

Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.

DOI: https://doi.org/10.1038/s41580-023-00606-x
J Thorac Cardiovasc Surg. 2023 May 19. pii: S0022-5223(23)00434-8. [Epub ahead of print]

Mitochondrial Transplantation Preserves Myocardial Function and Viability in Pediatric and Neonatal Donation After Circulatory Death Pig Hearts.

Victor S Alemany, Rio Nomoto, Mossab Y Saeed, Aybuke Celik, William L Regan, Gregory S Matte, Dominic P Recco, Sitaram M Emani, Pedro J Del Nido, James D McCully.

  OBJECTIVE: Mitochondrial transplantation has been shown to preserve myocardial function and viability in porcine DCD adult hearts. Herein, we investigate the efficacy of mitochondrial transplantation for the preservation of myocardial function and viability in neonatal and pediatric porcine DCD heart donation.METHODS: Circulatory death was induced in neonatal and pediatric Yorkshire pigs by cessation of mechanical ventilation. Hearts underwent 20 or 36 min. of warm ischemia time (WIT), 10 min. of cold cardioplegic arrest and then were harvested for ex-situ heart perfusion (ESHP). Following 15 min. of ESHP, hearts received either vehicle (VEH) or vehicle containing isolated autologous mitochondria (MITO). A sham non-ischemic group (SHAM) did not undergo WIT mimicking donation after brain death (DBD) heart procurement. Hearts underwent 2 hr. each of unloaded and loaded ESHP perfusion.
RESULTS: Following 4 hr. ESHP perfusion, LVDP, dP/dt max, and fractional shortening were significantly decreased (P< 0.001) in DCD hearts receiving VEH compared to Sham hearts. In contrast, DCD hearts receiving MITO exhibited significantly preserved LVDP, dP/dt max, and fractional shortening (P<0.001 each vs VEH, not significant vs SHAM). Infarct size was significantly decreased in DCD hearts receiving MITO as compared to VEH (P< 0.001). Pediatric DCD hearts subjected to extended WIT demonstrated significantly preserved fractional shortening and significantly decreased infarct size with MITO (P< 0.01 each vs VEH).
CONCLUSIONS: Mitochondrial transplantation in neonatal and pediatric pig DCD heart donation significantly enhances the preservation of myocardial function and viability and mitigates against damage secondary to extended WIT.

Keywords:  Donation after circulatory death; Heart transplant; Ischemia; Mitochondrial transplantation; Neonatal; Pediatric

DOI:  https://doi.org/10.1016/j.jtcvs.2023.05.010
Nucleic Acids Res. 2023 May 22. pii: gkad441. [Epub ahead of print]

Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers.

Anastasia Rastokina, Jorge Cebrián, Negin Mozafari, Nicholas H Mandel, C I Edvard Smith, Massimo Lopes, Rula Zain, Sergei M Mirkin.

Friedreich's ataxia (FRDA) is caused by expansions of GAA•TTC repeats in the first intron of the human FXN gene that occur during both intergenerational transmissions and in somatic cells. Here we describe an experimental system to analyze large-scale repeat expansions in cultured human cells. It employs a shuttle plasmid that can replicate from the SV40 origin in human cells or be stably maintained in S. cerevisiae utilizing ARS4-CEN6. It also contains a selectable cassette allowing us to detect repeat expansions that accumulated in human cells upon plasmid transformation into yeast. We indeed observed massive expansions of GAA•TTC repeats, making it the first genetically tractable experimental system to study large-scale repeat expansions in human cells. Further, GAA•TTC repeats stall replication fork progression, while the frequency of repeat expansions appears to depend on proteins implicated in replication fork stalling, reversal, and restart. Locked nucleic acid (LNA)-DNA mixmer oligonucleotides and peptide nucleic acid (PNA) oligomers, which interfere with triplex formation at GAA•TTC repeats in vitro, prevented the expansion of these repeats in human cells. We hypothesize, therefore, that triplex formation by GAA•TTC repeats stall replication fork progression, ultimately leading to repeat expansions during replication fork restart.

DOI: https://doi.org/10.1093/nar/gkad441
Antioxidants (Basel). 2023 May 10. pii: 1075. [Epub ahead of print]12(5):

PGC-1α Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response.

Othman Abu Shelbayeh, Tasnim Arroum, Silke Morris, Karin B Busch.

  Mitochondria play a major role in ROS production and defense during their life cycle. The transcriptional activator PGC-1α is a key player in the homeostasis of energy metabolism and is therefore closely linked to mitochondrial function. PGC-1α responds to environmental and intracellular conditions and is regulated by SIRT1/3, TFAM, and AMPK, which are also important regulators of mitochondrial biogenesis and function. In this review, we highlight the functions and regulatory mechanisms of PGC-1α within this framework, with a focus on its involvement in the mitochondrial lifecycle and ROS metabolism. As an example, we show the role of PGC-1α in ROS scavenging under inflammatory conditions. Interestingly, PGC-1α and the stress response factor NF-κB, which regulates the immune response, are reciprocally regulated. During inflammation, NF-κB reduces PGC-1α expression and activity. Low PGC-1α activity leads to the downregulation of antioxidant target genes resulting in oxidative stress. Additionally, low PGC-1α levels and concomitant oxidative stress promote NF-κB activity, which exacerbates the inflammatory response.

Keywords:  PGC-1α; ROS defense; mitochondrial life cycle; mitonuclear communication

DOI:  https://doi.org/10.3390/antiox12051075
Nature. 2023 May 24.

Mother's milk helps baby mouse hearts to develop.

Elissa Welle.



Keywords:  Cardiovascular biology; Developmental biology; Nutrition

DOI:  https://doi.org/10.1038/d41586-023-01699-2
Front Pharmacol. 2023 ;14 1117337

Mitochondrial dysfunction-targeting therapeutics of natural products in Parkinson's disease.

Ting He, Xiaoyan Lin, Anping Su, Yujie Zhang, Zhichao Xing, Li Mi, Tao Wei, Zhihui Li, Wenshuang Wu.

  Parkinson's disease (PD), the second most common neurodegenerative disease worldwide, often occurs in middle-aged and elderly individuals. The pathogenesis of PD is complex and includes mitochondrial dysfunction, and oxidative stress. Recently, natural products with multiple structures and their bioactive components have become one of the most important resources for small molecule PD drug research targeting mitochondrial dysfunction. Multiple lines of studies have proven that natural products display ameliorative benefits in PD treatment by regulating mitochondrial dysfunction. Therefore, a comprehensive search of recent published articles between 2012 and 2022 in PubMed, Web of Science, Elesvier, Wliey and Springer was carried out, focusing on original publications related to natural products against PD by restoring mitochondrial dysfunction. This paper presented the mechanisms of various kinds of natural products on PD-related mitochondrial dysfunction regulation and provided evidence that natural products are promising to be developed as drugs for PD therapeutics.

Keywords:  Parkinson’s disease; flavanoids; mitochondrial dysfunction; natural products; pharmacological mechanisms; phenols

DOI:  https://doi.org/10.3389/fphar.2023.1117337
Neurobiol Dis. 2023 May 18. pii: S0969-9961(23)00171-7. [Epub ahead of print]183 106157

A mitochondrial-targeted antioxidant (MitoQ) improves motor coordination and reduces Purkinje cell death in a mouse model of ARSACS.

Brenda Toscano Márquez, Tsz Chui Sophia Leung, Jeanette Hui, François Charron, R Anne McKinney, Alanna J Watt.

  Mitochondrial deficits have been observed in animal models of Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and in patient-derived fibroblasts. We investigated whether mitochondrial function could be restored in Sacs-/- mice, a mouse model of ARSACS, using the mitochondrial-targeted antioxidant ubiquinone MitoQ. After 10weeks of chronic MitoQ administration in drinking water, we partially reversed motor coordination deficits in Sacs-/- mice but did not affect litter-matched wild-type control mice. MitoQ administration led to a restoration of superoxide dismutase 2 (SOD2) in cerebellar Purkinje cell somata without altering Purkinje cell firing deficits. Purkinje cells in anterior vermis of Sacs-/- mice normally undergo cell death in ARSACS; however, Purkinje cells numbers were elevated after chronic MitoQ treatment. Furthermore, Purkinje cell innervation of target neurons in the cerebellar nuclei of Sacs-/- mice was also partially restored with MitoQ treatment. Our data suggest that MitoQ is a potential therapeutic treatment for ARSACS and that it improves motor coordination via increasing cerebellar Purkinje cell mitochondria function and reducing Purkinje cell death.

Keywords:  ARSACS; Ataxia; Autosomal-recessive spastic ataxia of the Charlevoix-Saguenay; Cerebellar nuclei; Cerebellum; MitoQ; Mitochondria; Mouse model of disease; Purkinje cell

DOI:  https://doi.org/10.1016/j.nbd.2023.106157
Nat Commun. 2023 May 22. 14(1): 2740

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration.

Eva Crosas-Molist, Vittoria Graziani, Oscar Maiques, Pahini Pandya, Joanne Monger, Remi Samain, Samantha L George, Saba Malik, Jerrine Salise, Valle Morales, Adrien Le Guennec, R Andrew Atkinson, Rosa M Marti, Xavier Matias-Guiu, Guillaume Charras, Maria R Conte, Alberto Elosegui-Artola, Mark Holt, Victoria Sanz-Moreno.

Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.

DOI: https://doi.org/10.1038/s41467-023-38292-0
Nat Commun. 2023 May 24. 14(1): 2994

Redefining the role of AMPK in autophagy and the energy stress response.

Ji-Man Park, Da-Hye Lee, Do-Hyung Kim.

Autophagy maintains cellular homeostasis during low energy states. According to the current understanding, glucose-depleted cells induce autophagy through AMPK, the primary energy-sensing kinase, to acquire energy for survival. However, contrary to the prevailing concept, our study demonstrates that AMPK inhibits ULK1, the kinase responsible for autophagy initiation, thereby suppressing autophagy. We found that glucose starvation suppresses amino acid starvation-induced stimulation of ULK1-Atg14-Vps34 signaling via AMPK activation. During an energy crisis caused by mitochondrial dysfunction, the LKB1-AMPK axis inhibits ULK1 activation and autophagy induction, even under amino acid starvation. Despite its inhibitory effect, AMPK protects the ULK1-associated autophagy machinery from caspase-mediated degradation during energy deficiency, preserving the cellular ability to initiate autophagy and restore homeostasis once the stress subsides. Our findings reveal that dual functions of AMPK, restraining abrupt induction of autophagy upon energy shortage while preserving essential autophagy components, are crucial to maintain cellular homeostasis and survival during energy stress.

DOI: https://doi.org/10.1038/s41467-023-38401-z
Antioxidants (Basel). 2023 May 10. pii: 1072. [Epub ahead of print]12(5):

Metabolic Priming as a Tool in Redox and Mitochondrial Theragnostics.

Sónia A Pinho, Sandra I Anjo, Teresa Cunha-Oliveira.

  Theragnostics is a promising approach that integrates diagnostics and therapeutics into a single personalized strategy. To conduct effective theragnostic studies, it is essential to create an in vitro environment that accurately reflects the in vivo conditions. In this review, we discuss the importance of redox homeostasis and mitochondrial function in the context of personalized theragnostic approaches. Cells have several ways to respond to metabolic stress, including changes in protein localization, density, and degradation, which can promote cell survival. However, disruption of redox homeostasis can lead to oxidative stress and cellular damage, which are implicated in various diseases. Models of oxidative stress and mitochondrial dysfunction should be developed in metabolically conditioned cells to explore the underlying mechanisms of diseases and develop new therapies. By choosing an appropriate cellular model, adjusting cell culture conditions and validating the cellular model, it is possible to identify the most promising therapeutic options and tailor treatments to individual patients. Overall, we highlight the importance of precise and individualized approaches in theragnostics and the need to develop accurate in vitro models that reflect the in vivo conditions.

Keywords:  media composition; metabolic priming; mitochondria; oxygen levels; redox homeostasis; theragnostics

DOI:  https://doi.org/10.3390/antiox12051072
Front Neurol. 2023 ;14 1151835

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction.

Omri Bar, Laurie Ebenau, Kellee Weiner, Mark Mintz, Richard G Boles.

  Objective: To utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting.Methods: A retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed. "Qualifying" variants were defined as coding, rare, and conserved. Additionally, "Key Qualifying" variants were Pathogenic/Likely Pathogenic, or "Clinical" based upon the presence of a corresponding diagnosis. Candidate association to CVS was based on a point system.
Results: Thirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as "Highly likely" (SCN4A, CACNA1A, CACNA1S, RYR2, TRAP1, MEFV) or "Likely" (SCN9A, TNFRSF1A, POLG, SCN10A, POGZ, TRPA1) CVS related. Nine additional genes (OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3, PPM1D, CHAMP1, HMBS) had sufficient evidence in the literature but not from our study participants. Candidate status for mitochondrial DNA was confirmed by the literature and our study data. Among the above-listed 22 CVS candidate genes, a Key Qualifying variant was identified in 31/80 (34%), and any Qualifying variant was present in 61/80 (76%) of participants. These findings were highly statistically significant (p < 0.0001, p = 0.004, respectively) compared to an alternative hypothesis/control group regarding brain neurotransmitter receptor genes. Additional, post-analyses, less-intensive review of all genes (exome) outside our paroxysmal genes identified 13 additional genes as "Possibly" CVS related.
Conclusion: All 22 CVS candidate genes are associated with either cation transport or energy metabolism (14 directly, 8 indirectly). Our findings suggest a cellular model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle of cellular hyperexcitability. Among the non-paroxysmal genes identified, 5 are known causes of peripheral neuropathy. Our model is consistent with multiple current hypotheses of CVS.

Keywords:  aberrant ion gradients; cellular hyperexcitation; cyclic vomiting syndrome; migraine variants; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fneur.2023.1151835