Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA-cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNAB6 and mtDNANZB, where mtDNANZB mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNAB6 Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas mtDNANZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNANZB mice exhibited strikingly impaired tumor growth while mtDNAB6 mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNANZB Teff cells increased mitochondrial gene expression while activation of mtDNANZB Treg cells impaired mitochondrial gene expression and resulted in mtDNANZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNANZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.

Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons regulate morphological and physiological properties of brown and beige fat and prevent systemic hypermetabolism. Targeting runt-related transcription factor 3 (Runx3)/parvalbumin (PV) sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat-diet-induced obesity, and caused adipose tissue browning and beiging, likely driven by elevated norepinephrine levels. Finding that brown and beige fat are innervated by Runx3/PV sensory neurons expressing Piezo2 suggests a model in which mechanical signals, sensed by Piezo2 in sensory neurons, protect energy storage and prevent a systemic hypermetabolic phenotype.

Dihydrolipoamide dehydrogenase (DLD) deficiency (MIM #246900) is a rare autosomal recessive mitochondrial disorder caused by pathogenic variants in the DLD gene, which encodes the E3 subunit common to multiple mitochondrial enzyme complexes, including pyruvate dehydrogenase (PDHc) and α-ketoglutarate dehydrogenase (αKGDHc). Although genotype-phenotype correlations have been described, the precise bioenergetic consequences of DLD dysfunction remain poorly defined. Here, we applied high-resolution respirometry using a novel single-run protocol that allows simultaneous assessment of mitochondrial respiratory capacity and, critically, distinguishing between PDHc- and αKGDHc-linked respiration within the same assay. Fibroblasts from six genetically confirmed DLD-deficient patients with distinct pathogenic variants and clinical severities exhibited a consistent reduction in maximal and complex I-linked respiration. The most severe cases (c.1436A>T; p.D479V) showed combined PDHc and αKGDHc impairment, whereas milder genotypes displayed isolated PDHc dysfunction. This mechanistic distinction likely underlies the variable clinical response to ketogenic therapy, which depends on intact αKGDHc function. Analysis of the mitochondrial mass and mtDNA copy number revealed no global reduction, indicating intrinsic enzymatic dysfunction as the primary defect. Collectively, this study defines a reproducible bioenergetic signature of DLD deficiency and introduces an integrated one-run diagnostic strategy for delineating enzyme-specific mitochondrial defects, providing a framework for mechanistic and therapeutic investigations.

CD19 CAR-T cells have led to durable remissions in patients with refractory B-cell malignancies; nevertheless, most patients eventually relapse in the long term. Many interventions aimed at improving current products have been reported, with a subset of them focusing on a direct or indirect link to the metabolic state of the CAR-T cells. We assessed clinical products from an ongoing clinical trial utilizing CD19-28z CAR-T cells from patients with acute lymphoblastic leukemia. CAR-T clinical products leading to a complete response had significantly higher mitochondrial function (by oxygen consumption rate) irrespective of mitochondrial content. Next, we replaced the carbon source of the media from glucose to galactose to impact cellular metabolism. Galactose-containing media increased mitochondrial activity in CAR-T cells, and improved in vitro efficacy, without any consistent phenotypic change in memory profile. Finally, CAR-T cells produced in galactose-based glucose-free media resulted in increased mitochondrial activity. Using an in vivo model of Nalm6 injected mice, galactose-primed CAR-T cells significantly improved leukemia-free survival compared to standard glucose-cultured CAR-T cells. Our results prove the significance of mitochondrial metabolism on CAR-T cell efficacy and suggest a translational pathway to improve clinical products.

Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons inhibit thermogenesis and prevent systemic hypermetabolism. Targeting Runx3/PV sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat diet-induced obesity and increased thermogenic fat activity, likely driven by elevated norepinephrine levels. Finding that thermogenic fat is innervated by Runx3/PV sensory neurons expressing Piezo2, suggests a model where mechanical signals sensed by Piezo2 in sensory neurons protect energy storages and inhibit adipose thermogenesis. ### Competing Interest Statement The authors have declared no competing interest.

Summary Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. We have analyzed the exercise physiology of mice deficient in ANT1, demonstrating a peripheral limitation of skeletal muscle mitochondrial respiration. Upon exercise, lack of Nicotinamide adenine dinucleotide + (NAD + ) results in a substrate limitation and stalling of the TCA cycle and mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD + levels in skeletal muscle and improved the exercise capacity and mitochondrial respiration. Thus, increasing NAD + levels with nicotinamide riboside can alleviate the exercise intolerance associated with ANT1-deficiency, indicating the therapeutic potential of NAD + -stimulating compounds in specific mitochondrial myopathies.

Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.

Mitochondrial dysfunction is associated with a range of clinical manifestations including neuropsychiatric and metabolic disorder. Here, we reanalyzed a family with an L-Histidine Decarboxylase (HDC) variant previously linked to Tourette syndrome but with associated connective tissue and metabolic features of unknown etiology. We identified a mitochondrial haplogroup J-defining mutation on the haplogroup H background that functionally interacts with the L-Histidine Decarboxylase variant via calcium homeostasis. Our findings establish how a common mtDNA variant on a different mtDNA background can result in mitochondrial dysfunction, demonstrate a role for histaminergic signaling in modifying mitochondrial phenotypes, and link mitochondria dysfunction to connective tissue phenotypes.

Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations.

European Journal of NeuroscienceVolume 53, Issue 9 p. 2943-2945 EDITORIALFree Access Powering the brain in health and disease Tamas Kozicz, Corresponding Author Tamas Kozicz [email protected] orcid.org/0000-0001-6915-4364 Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA Canter for Individualized Medicine, Mayo Clinic, Rochester, MN, USA Correspondence Tamas Kozicz, Department of Clinical Genomics-Department of Laboratory Medicine and Pathology, Mayo Clinic-200 First Street, SW, Rochester, MN 55905, USA. Email: [email protected]Search for more papers by this authorEva Morava, Eva Morava Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA Canter for Individualized Medicine, Mayo Clinic, Rochester, MN, USASearch for more papers by this authorTal Yardeni, Tal Yardeni Children's Hospital of Philadelphia Research Institute, Center for Mitochondrial and Epigenomic Medicine, Philadelphia, PA, USASearch for more papers by this author Tamas Kozicz, Corresponding Author Tamas Kozicz [email protected] orcid.org/0000-0001-6915-4364 Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA Canter for Individualized Medicine, Mayo Clinic, Rochester, MN, USA Correspondence Tamas Kozicz, Department of Clinical Genomics-Department of Laboratory Medicine and Pathology, Mayo Clinic-200 First Street, SW, Rochester, MN 55905, USA. Email: [email protected]Search for more papers by this authorEva Morava, Eva Morava Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA Canter for Individualized Medicine, Mayo Clinic, Rochester, MN, USASearch for more papers by this authorTal Yardeni, Tal Yardeni Children's Hospital of Philadelphia Research Institute, Center for Mitochondrial and Epigenomic Medicine, Philadelphia, PA, USASearch for more papers by this author First published: 16 April 2021 https://doi.org/10.1111/ejn.15230 Edited by: Yoland Smiths AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL 1 INTRODUCTION Neuropsychiatric disorders are complex brain diseases and are the leading cause of morbidity and mortality. Despite decades of research, the underlying etiology(ies) remains largely elusive. Although various environmental adversities have been causally linked to the development of neuropsychiatric diseases, why some individuals are more vulnerable to these environmental adversities, while others exhibit relative resilience is still poorly understood (Picard & Sandi, 2021). For this special issue, we have put together a series of empirical papers and targeted reviews that describe our latest understanding of brain energetics in health and disease. In the last decade, a compelling body of evidence has been gathered supporting the significance of mitochondrial dysfunction underpinning individual differences to susceptibility to neuropsychiatric diseases (Johnson et al., 2020; Morava & Kozicz, 2013; Pei & Wallace, 2018; Preston et al., 2018; Wallace, 2018). Specifically, subtle changes in mitochondrial functions due to mild systemic mitochondrial defects (mtDNA ND6P25L) in mice can result in autism spectrum disorder that includes impaired social interactions, increased repetitive behaviors, and anxiety (Yardeni et al., 2021). Impaired mitochondrial function can result from primary mitochondrial diseases​ or secondary mitochondrial dsyfunction (PMD, SMD, respectively). PMD is genetically defined and diagnosed by identifying mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that result in mitochondrial dysfunction. SMD essentially refers to abnormal mitochondrial function other than PMD, and often accompany many hereditary nonmitochondrial diseases. SMD may also be due to nongenetic causes such as environmental factors (Rahman & Rahman, 2018; Rahman, 2018; Russell et al., 2020). The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established (Borsche et al., 2021; Johnson et al., 2020; Prasuhn et al., 2020). Compelling evidence indicates that the presence of alpha-synuclein(α-Syn) is associated with mitochondrial dysfunction and oxidative stress. Similarly, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Feng et al. provide a comprehensive overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria (Feng et al., 2020). Investigating the role of mitochondria in neuronal cell types has dominated the field. Mitochondrial (dys)function in non-neuronal cells; such as astrocytes has been overshadowed by neuronal mitochondria (Bantle et al., 2020; Miyazaki & Asanuma, 2020), which are responsible for the bulk of oxidative metabolism in the brain. In this special issue, Bagnoli et al. report on the significance of astrocyte mitochondrial function in neurodegenerative diseases (Bagnoli et al., 2020). They provide evidence that the monoamine oxidase metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde(DOPAL) has a significant effect on astrocyte viability, reactivity and mitochondrial function. They found that DOPAL not only significantly reduced Neu7 viability and induced apoptosis, but also decreased mitochondrial performance and increased oxidative and nitrative stress. This study is the first evidence that DOPAL is directly toxic to astrocytes. The loss of astrocyte viability and the gain of neurotoxic effects have detrimental consequences on neuronal viability. This research supports the notion that secondary mitochondrial dysfunction induced by DOPAL may contribute to neurodegenerative diseases, such as Parkinson's disease. Brain mitochondrial function is not only critical for resilience, but also for numerous neuronal and behavioral processes. A link between brain bioenergetics and social dominance has been proposed and higher levels of mitochondrial function supports increased social competitive ability (Hollis et al., 2017; van der Kooij et al., 2018; Picard et al., 2018). Guillot de Susurrant et al. set out to study the underlying mechanism of this link (Guillot de Suduiraut et al., 2020). They investigated the contribution of astrocytic release of adenosine triphosphate (ATP) through the type 2 inositol 1,4,5-triphosphate receptor to social dominance behavior. Mice that lack the type 2 inositol 1,4,5-triphosphate receptor presented with similar competitive ability and exhibited a significant delay in exerting their dominance during the initial encounter. Their findings point to a marginal role of astrocytic through IP3R2 in social competition, suggesting that, under basal conditions, the neuronal compartment is predominant for social dominance exertion. Several studies suggested that medications to treat neuropsychiatric disorders could directly influence mitochondrial function (Adzic et al., 2016; Hargreaves et al., 2016; Karabatsiakis & Schönfeldt-Lecuona, 2020; Pope & Wood, 2020). Emmerzaal et al. used a mouse model for trait suboptimal mitochondrial function (SMF) to test the hypothesis that chronic fluoxetine treatment would negatively, whereas chronic ketamine treatment would positively impact brain bioenergetics of WT and SMF mice subjected to chronic stress (Emmerzaal et al., 2020).. Emmerzaal et al. provide compelling evidence that chronic fluoxetine treatment negatively impacted brain bioenergetics. In contrast, ketamine did not significantly influence brain mitochondrial function. These studies are interesting as they suggest that individual differences in brain bioenergetics could be a moderator of an individual's response to antidepressant treatment. A review by Vlaikou et al. discusses changes in the interplay between glycolysis and mitochondrial energy metabolism in psychiatric disorders and brain tumors (Vlaikou et al., 2020). They discuss alterations in glycolysis versus core mitochondrial metabolic pathways, such as the tricarboxylic acid cycle and oxidative phosphorylation. They identify potential common patterns of altered mitochondrial metabolism in different brain regions and cell types and explore how changes in mitochondrial number, shape and morphology affect disease-related manifestations. The studies presented in this special issue examined energy production and consumption as a special case of system vulnerability for the brain. These studies also raise awareness on the significance of brain bioenergetics in health and disease, highlight the potential of pharmacologically targeting mitochondria not only to find novel therapeutic approaches in neuropsychiatric diseases, but also to ensure that such treatments are tailored to the needs of the individual. Open Research PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/ejn.15230. 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Neuroscience and Biobehavioral Reviews, 116, 337– 349. https://doi.org/10.1016/j.neubiorev.2020.06.031 Prasuhn, J., Davis, R. L., & Kumar, K. R. (2020). Targeting mitochondrial impairment in Parkinson's disease: Challenges and opportunities. Frontiers in Cell and Developmental Biology, 8, 615461. https://doi.org/10.3389/fcell.2020.615461 Preston, G., Kirdar, F., & Kozicz, T. (2018). The role of suboptimal mitochondrial function in vulnerability to post-traumatic stress disorder. Journal of Inherited Metabolic Disease, 41, 585– 596. https://doi.org/10.1007/s10545-018-0168-1 Rahman, J., & Rahman, S. (2018). Mitochondrial medicine in the omics era. Lancet, 391, 2560– 2574. https://doi.org/10.1016/S0140-6736(18)30727-X Rahman, S. (2018). Mitochondrial diseases and status epilepticus. Epilepsia, 59(Suppl 2), 70– 77. https://doi.org/10.1111/epi.14485 Russell, O. M., Gorman, G. S., Lightowlers, R. N., & Turnbull, D. M. (2020). Mitochondrial diseases: Hope for the future. Cell, 181, 168– 188. https://doi.org/10.1016/j.cell.2020.02.051 van der Kooij, M. A., Hollis, F., Lozano, L., Zalachoras, I., Abad, S., Zanoletti, O., Grosse, J., Guillot de Suduiraut, I., Canto, C., & Sandi, C. (2018). Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors. Molecular Psychiatry, 23, 569– 578. https://doi.org/10.1038/mp.2017.135 Vlaikou, A. M., Nussbaumer, M., Komini, C., Lambrianidou, A., Konidaris, C., Trangas, T., & Filiou, M. D. (2020). Exploring the crosstalk of glycolysis and mitochondrial metabolism in psychiatric disorders and brain tumours. European Journal of Neuroscience. https://doi.org/10.1111/ejn.15057 Wallace, D. C. (2018). Mitochondrial genetic medicine. Nature Genetics, 50, 1642– 1649. https://doi.org/10.1038/s41588-018-0264-z Yardeni, T., Cristancho, A. G., McCoy, A. J., Schaefer, P. M., McManus, M. J., Marsh, E. D., & Wallace, D. C. (2021). An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes. Proceedings of the National Academy of Sciences of the United States of America, 118. Volume53, Issue9Powering the Brain in Health and DiseaseMay 2021Pages 2943-2945 ReferencesRelatedInformation

Changes in the gut microbiota and the mitochondrial genome are both linked with the development of disease. To investigate why, we examined the gut microbiota of mice harboring various mutations in genes that alter mitochondrial function. These studies revealed that mitochondrial genetic variations altered the composition of the gut microbiota community. In cross-fostering studies, we found that although the initial microbiota community of newborn mice was that obtained from the nursing mother, the microbiota community progressed toward that characteristic of the microbiome of unfostered pups of the same genotype within 2 months. Analysis of the mitochondrial DNA variants associated with altered gut microbiota suggested that microbiome species diversity correlated with host reactive oxygen species (ROS) production. To determine whether the abundance of ROS could alter the gut microbiota, mice were aged, treated with N -acetylcysteine, or engineered to express the ROS scavenger catalase specifically within the mitochondria. All three conditions altered the microbiota from that initially established. Thus, these data suggest that the mitochondrial genotype modulates both ROS production and the species diversity of the gut microbiome, implying that the connection between the gut microbiome and common disease phenotypes might be due to underlying changes in mitochondrial function.

Introduction: Sialic acids are important contributors to the polyanionic component of the glomerular filtration barrier, which regulates permeability selectivity. Pathologic glomerular hyposialylation, associated with podocyte effacement, has been implicated in human and mouse glomerulopathies. Oral treatment with N-acetylmannosamine (ManNAc), the uncharged precursor of sialic acid, ameliorates glomerular pathology in different models of glomerular disease. Methods: Here we explore the sialylation status of kidney biopsies obtained from 27 subjects with various glomerular diseases using lectin histochemistry. Results: We identified severe glomerular hyposialylation in 26% of the biopsies. These preliminary findings suggest that this condition may occur relatively frequently and may be a novel target for therapy. We describe the background, rationale, and design of a phase 1 study to test safety, tolerability, and pharmacokinetics of ManNAc in subjects with primary podocyte diseases. Conclusion: We recently demonstrated that ManNAc was safe and well tolerated in a first-in-human phase 1 study in subjects with UDP-N-acetylglucosamine (GIcNAc) 2-epimerase/ManNAc kinase (GNE) myopathy, a disorder of impaired sialic acid synthesis. Using previous preclinical and clinical data, we propose to test ManNAc therapy for subjects with primary glomerular diseases. Even though the exact mechanisms, affected cell types, and pathologic consequences of glomerular hyposialylation need further study, treatment with this physiological monosaccharide could potentially replace or supplement existing glomerular diseases therapies.

microRNAs (miRNAs) are critical for neuronal function and their dysregulation is repeatedly observed in neurodegenerative diseases. Here, we implemented high content image analysis for investigating the impact of several miRNAs in mouse primary motor neurons. This survey directed our attention to the neuron-specific miR-124, which controls axonal morphology. By performing next generation sequencing analysis and molecular studies, we characterized novel roles for miR-124 in control of mitochondria localization and function. We further demonstrated that the intermediate filament Vimentin is a key target of miR-124 in this system. Our data establishes a new pathway for control of mitochondria function in motor neurons, revealing the value of a neuron-specific miRNA gene as a mechanism for the re-shaping of otherwise ubiquitously-expressed intermediate filament network, upstream of mitochondria activity and cellular metabolism.

Primary coenzyme Q10 (CoQ(10); MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ(10), and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ(10) synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. Whole-exome and subsequent whole-genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ(10) in peripheral white blood cells of all affected individuals and reduced CoQ(10) levels in the only muscle tissue available from one affected proband. CoQ(10) supplementation led to clinical improvement and increased the concentrations of CoQ(10) in blood. This is the first report of primary CoQ(10) deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological, and molecular features, and insights regarding targeted treatment with CoQ(10) supplementation.

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.