Mitochondrial Respiratory Chain Defects Research Articles

Upregulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain

Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional upregulation of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally downregulated in cellular and murine models of mitochondrial defects. We identified a role for the posttranscriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified invivo, using a model of mitochondria-associated disease in Caenorhabditis elegans that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.

Pathological role of high sugar in mitochondrial respiratory chain defect - augmented mitochondrial stress.

Respiratory complex anomalies could lead to the production of ROS. Ca2+, at physiological levels serves as a second messenger in many physiological functions. However, a research group reported that mitochondrial calcium [Ca2+]m overload leads to ROS production which could be lethal to the mitochondria through various mechanisms. The F1F0-ATPase (ATP synthase or complex V) is the enzyme that is responsible for catalyzing the final step of oxidative phosphorylation. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space thereby blocking ATP synthesis leading to Neuropathy, Ataxia and Retinitis Pigmentosa Syndromes (NARP). The main aim undertaking this study is to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain mediated mitochondrial stress. The NARP cybrids are ordered and are established in vitro experimental models for the cells with F1FO-ATPase defects, these cells harbor 98% of mtDNA T8993G mutation. Their counterparts 143B osteosarcoma cell lines are the parental cell lines used for comparisons. We uncovered that, NARP cells mediated and enhanced the death of the cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose respectively as depicted by the MTT assay of cell viability. Furthermore, using the fluorescence probe-coupled laser scanning confocal imaging microscopy, NARP cells significantly enabled mitochondrial reactive oxygen species (mROS) formation and enhanced the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar enhanced toxicity on mitochondria would help in the future to alleviate the symptoms of patients associated with Neuritis Ataxia Retinitis Pigmentosa (NARP) syndromes.

Multicentric Standardization of Protocols for the Diagnosis of Human Mitochondrial Respiratory Chain Defects.

The quantification of mitochondrial respiratory chain (MRC) enzymatic activities is essential for diagnosis of a wide range of mitochondrial diseases, ranging from inherited defects to secondary dysfunctions. MRC lesion is frequently linked to extended cell damage through the generation of proton leak or oxidative stress, threatening organ viability and patient health. However, the intrinsic challenge of a methodological setup and the high variability in measuring MRC enzymatic activities represents a major obstacle for comparative analysis amongst institutions. To improve experimental and statistical robustness, seven Spanish centers with extensive experience in mitochondrial research and diagnosis joined to standardize common protocols for spectrophotometric MRC enzymatic measurements using minimum amounts of sample. Herein, we present the detailed protocols, reference ranges, tips and troubleshooting methods for experimental and analytical setups in different sample preparations and tissues that will allow an international standardization of common protocols for the diagnosis of MRC defects. Methodological standardization is a crucial step to obtain comparable reference ranges and international standards for laboratory assays to set the path for further diagnosis and research in the field of mitochondrial diseases.

Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?

Parkinson’s disease (PD) is the most common age-dependent neurodegenerative synucleinopathy. Loss of dopaminergic neurons of the substantia nigra pars compacta, together with region- and cell-specific aggregations of -synuclein are considered main pathological hallmarks of PD, but its etiopathogenesis remains largely unknown. Mitochondrial dysfunction, in particular quantitative and/or functional deficiencies of the mitochondrial respiratory chain (MRC), has been associated with the disease. However, after decades of research in this field, the pervasiveness and anatomical extent of MRC dysfunction in PD remain largely unknown. Moreover, it is not known whether the observed MRC defects are pathogenic, compensatory responses, or secondary epiphenomena. In this perspective, we give an overview of current evidence for MRC dysfunction in PD, highlight pertinent knowledge gaps, and propose potential strategies for future research.

Mitochondrial hepatopathy: Respiratory chain disorders- 'breathing in and out of the liver'.

Mitochondria, the powerhouse of a cell, are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond. Evolution supports a prokaryotic descent, and, unsurprisingly, the organelle is worthy of being labeled an organism in itself. Since highly metabolically active organs require a continuous feed of energy, any dysfunction in the structure and function of mitochondria can have variable impact, with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition. Though categorized a hepatopathy, mitochondrial respiratory chain defects are not limited to the liver in time and space. The liver involvement is also variable in clinical presentation as well as in age of onset, from acute liver failure, cholestasis, or chronic liver disease. Other organs like eye, muscle, central and peripheral nervous system, gastrointestinal tract, hematological, endocrine, and renal systems are also variably involved. Diagnosis hinges on recognition of subtle clinical clues, screening metabolic investigations, evaluation of the extra-hepatic involvement, and role of genetics and tissue diagnosis. Treatment is aimed at both circumventing the acute metabolic crisis and long-term management including nutritional rehabilitation. This review lists and discusses the burden of mitochondrial respiratory chain defects, including various settings when to suspect, their evolution with time, including certain specific disorders, their tiered evaluation with diagnostic algorithms, management dilemmas, role of liver transplantation, and the future research tools.

A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome

Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial deficiency. m.14597A>G (p.Ile26Thr) in the MT-ND6 gene was reported to cause Leberʼs hereditary optic neuropathy (LHON) or dementia/dysarthria. In previous reports, less than 90% heteroplasmy was shown to result in adult-onset disease. Here, by whole mitochondrial sequencing, we identified m.14597A>G mutation of a patient with LS. PCR–RFLP analysis on fibroblasts from the patient revealed a high mutation load (> 90% heteroplasmy). We performed functional assays using cybrid cell models generated by fusing mtDNA-less rho0 HeLa cells with enucleated cells from patient fibroblasts carrying the m.14597A>G variant. Cybrid cell lines bearing the m.14597A>G variant exhibited severe effects on mitochondrial complex I activity. Additionally, impairment of cell proliferation, decreased ATP production and reduced oxygen consumption rate were observed in the cybrid cell lines bearing the m.14597A>G variant when the cells were metabolically stressed in medium containing galactose, indicating mitochondrial respiratory chain defects. These results suggest that a high mutation load of m.14597A>G leads to LS via a mitochondrial complex I defect, rather than LHON or dementia/dysarthria.

Regulation of Mitochondrial Quality Control by Natural Drugs in the Treatment of Cardiovascular Diseases: Potential and Advantages.

Mitochondria are double-membraned cellular organelles that provide the required energy and metabolic intermediates to cardiomyocytes. Mitochondrial respiratory chain defects, structure abnormalities, and DNA mutations can affect the normal function of cardiomyocytes, causing an imbalance in intracellular calcium ion homeostasis, production of reactive oxygen species, and apoptosis. Mitochondrial quality control (MQC) is an important process that maintains mitochondrial homeostasis in cardiomyocytes and involves multi-level regulatory mechanisms, such as mitophagy, mitochondrial fission and fusion, mitochondrial energy metabolism, mitochondrial antioxidant system, and mitochondrial respiratory chain. Furthermore, MQC plays a role in the pathological mechanisms of various cardiovascular diseases (CVDs). In recent years, the regulatory effects of natural plants, drugs, and active ingredients on MQC in the context of CVDs have received significant attention. Effective active ingredients in natural drugs can influence the production of energy-supplying substances in the mitochondria, interfere with the expression of genes associated with mitochondrial energy requirements, and regulate various mechanisms of MQC modulation. Thus, these ingredients have therapeutic effects against CVDs. This review provides useful information about novel treatment options for CVDs and development of novel drugs targeting MQC.

Choroby mitochondrialne — co powinien wiedzieć kardiolog?

Mitochondrial diseases (MD) are a heterogeneous group of rare genetically determined disorders, characterized by mitochondrial respiratory chain defect and subsequent energy metabolism imbalance. Due to almost exclusive aerobic metabolism of the heart, cardiac involvement in MD is common and can be accompanied by other manifestations of the multi-organ involvement, but may be also the first or the sole clinical manifestation of MD. All tissues of the heart may be affected but the most frequently affected tissue is the myocardium. The most frequent cardiac manifestation found in MD are cardiomyopathies, but cardiac abnormalities may be varied and include arrhythmias, heart failure, pulmonary hypertension, dilation of the aortic root and pericardial effusion. Given the progressive nature of cardiac involvement in MD associated with poor prognosis and increased mortality and the fact that it can remain asymptomatic until an advanced stage is reached, often due to limited mobility of patients, cardiac screening should be a part of standard management of MD patients. All patients with cardiac involvement should be reviewed by a cardiologist with an experience and understanding of MD.

Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls

BackgroundComplex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts.ResultsWe showed that, other than ScNDI1, two different NDH-2 (AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells.ConclusionsIn conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.

Autophagy Induction by Bexarotene Promotes Mitophagy in Presenilin 1 Familial Alzheimer's Disease iPSC-Derived Neural Stem Cells.

Adult neurogenesis defects have been demonstrated in the brains of Alzheimer's disease (AD) patients. The neurogenesis impairment is an early critical event in the course of familiar AD (FAD) associated with neuronal loss. It was suggested that neurologic dysfunction in AD may be caused by impaired functioning of hippocampal neural stem cells (NSCs). Multiple metabolic and structural abnormalities in neural mitochondria have long been suspected to play a critical role in AD pathophysiology. We hypothesize that the cause of such abnormalities could be defective elimination of damaged mitochondria. In the present study, we evaluated mitophagy efficacy in a cellular AD model, hiPSC-derived NSCs harboring the FAD-associated PS1 M146L mutation. We found several mitochondrial respiratory chain defects such as lower expression levels of cytochrome c oxidase (complex IV), cytochrome c reductase (complex III), succinate dehydrogenase (complex II), NADH:CoQ reductase (complex I), and also ATP synthase (complex V), most of which had been previously associated with AD. The mitochondrial network morphology and abundance in these cells was aberrant. This was associated with a marked mitophagy failure stemming from autophagy induction blockage, and deregulation of the expression of proteins involved in mitochondrial dynamics. We show that treating these cells with autophagy-stimulating drug bexarotene restored autophagy and compensated mitochondrial anomalies in PS1 M146L NSCs, by enhancing the clearance of mitochondria. Our data support the hypothesis that pharmacologically induced mitophagy enhancement is a relevant and novel therapeutic strategy for the treatment of AD.

Mitochondrial Genetic Disorders: Cell Signaling and Pharmacological Therapies.

Mitochondrial fatty acid oxidation (FAO) and respiratory chain (RC) defects form a large group of inherited monogenic disorders sharing many common clinical and pathophysiological features, including disruption of mitochondrial bioenergetics, but also, for example, oxidative stress and accumulation of noxious metabolites. Interestingly, several transcription factors or co-activators exert transcriptional control on both FAO and RC genes, and can be activated by small molecules, opening to possibly common therapeutic approaches for FAO and RC deficiencies. Here, we review recent data on the potential of various drugs or small molecules targeting pivotal metabolic regulators: peroxisome proliferator activated receptors (PPARs), sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and protein kinase A (PKA)) or interacting with reactive oxygen species (ROS) signaling, to alleviate or to correct inborn FAO or RC deficiencies in cellular or animal models. The possible molecular mechanisms involved, in particular the contribution of mitochondrial biogenesis, are discussed. Applications of these pharmacological approaches as a function of genotype/phenotype are also addressed, which clearly orient toward personalized therapy. Finally, we propose that beyond the identification of individual candidate drugs/molecules, future pharmacological approaches should consider their combination, which could produce additive or synergistic effects that may further enhance their therapeutic potential.

Rapamycin as a potential treatment for succinate dehydrogenase deficiency

Drosophila melanogaster is a powerful model to study mitochondrial respiratory chain defects, particularly succinate dehydrogenase (SDH) deficiency. Mutations in sdh genes cause degenerative disorders and often lead to death. Therapies for such pathologies are based on a combination of vitamins and dietary supplements, and are rarely effective. In Drosophila, mutations in several of the genes encoding SDH resemble the pathology of SDH deficiency in humans, enabling the Drosophila model to be used in finding treatments for this condition. Here we show that exposure to the drug rapamycin improves the survival of sdh mutant strains, the activity of SDH and the impaired climbing associated with sdh mutations. However, the production of reactive oxygen species, the oxygen consumption of isolated mitochondria and the resistance to hyperoxia were minimally affected. Our results contribute to the current research seeking a treatment for mitochondrial disease.

Tribute to Linda Joanna DE MEIRLEIR

Tribute to Linda Joanna DE MEIRLEIR

MITOCHONDRIAL DISEASES (Posters): P.195A novel multiplex chromogenic immunoassay for evaluating mitochondrial respiratory chain complex I and complex IV defects in diagnostic muscle biopsies

The investigation of clinically suspected mitochondrial disease (mtD) includes performing a skeletal muscle biopsy for biochemical/histochemical assessment of mitochondrial respiratory chain (RC) defects. COX-SDH histochemistry detects RC-complex IV (CIV) defects, but RC-complex I (CI) defects cannot be detected histochemically. CI/CIV defects are common in mtD. Immunohistochemical evaluation of RC-complex defects relies on reduced amount of the assembled complex associated with catalytic deficiency, detectable with RC subunit-specific monoclonal antibodies. Our aim was to design a dual chromogenic immunoassay (DCI) for evaluating CI/CIV defects in diagnostic muscle biopsies. In the DCI optimised protocol, primary antibodies (Abcam), TOMM20 (mitochondrial mass), NDUFB8 (CI) and MTCO1 (CIV) were coincubated (TOMM20+CI and TOMM20+CIV), and then TOMM20 developed to yellow and the other marker to teal (Discovery/Ventana Systems) with colocalising antibodies visualising as green. Control sections stained as a mosaic dark green (type I fibres) and light green (type II fibres) pattern. Completely CI/CIV-deficient fibres stained yellow, and partly CI/CIV-deficient fibres stained yellow-green, and were easily detectable due to good visual colour contrast. The DCI and COX-SDH assays were performed in serial frozen sections. 23 biopsies were assessed: 15 with genetically confirmed mtD (mtDNA rearrangements/point mutations/depletion), 4 with high clinical/histological suspicion of mtD, and 4 unaffected controls. % COX and CI/CIV-deficient fibres were counted in two random fascicles, with high concordance amongst % COX-negative and CI/CIV-deficient fibres. The DCI detected more CI-deficient fibres in 7/19 cases and more CIV-deficient fibres in 5/19 cases compared to COX-negative fibres (average 6%). Most COX-negative fibres had dual CI+CIV defects with DCI. Segmental and partial CI/CIV defects were detectable. Equivocal COX-SDH stained fibres were often strongly CI/CIV-immunodeficient. In conclusion, our multiplex DCI reliably detects CI/CIV defects comparable in sensitivity to the COX-SDH histochemical assay, is easy to evaluate due to a good visual contrast between CI/CIV positive and negative fibres and can be easily co-opted to routine diagnostic work. Studies are underway to develop a quadruple chromogenic immunoassay for digital evaluation of CI/CIV defects.

Developmental arrest in Drosophila melanogaster caused by mitochondrial DNA replication defects cannot be rescued by the alternative oxidase

The xenotopic expression of the alternative oxidase AOX from the tunicate Ciona intestinalis in diverse models of human disease partially alleviates the phenotypic effects of mitochondrial respiratory chain defects. AOX is a non-proton pumping, mitochondrial inner membrane-bound, single-subunit enzyme that can bypass electron transport through the cytochrome segment, providing an additional site for ubiquinone reoxidation and oxygen reduction upon respiratory chain overload. We set out to investigate whether AOX expression in Drosophila could counteract the effects of mitochondrial DNA (mtDNA) replication defects caused by disturbances in the mtDNA helicase or DNA polymerase γ. We observed that the developmental arrest imposed by either the expression of mutant forms of these enzymes or their knockdown was not rescued by AOX. Considering also the inability of AOX to ameliorate the phenotype of tko25t, a fly mutant with mitochondrial translation deficiency, we infer that this alternative enzyme may not be applicable to cases of mitochondrial gene expression defects. Finding the limitations of AOX applicability will help establish the parameters for the future putative use of this enzyme in gene therapies for human mitochondrial diseases.

Ethanolamine ameliorates mitochondrial dysfunction in cardiolipin-deficient yeast cells

Cardiolipin (CL) is a signature phospholipid of the mitochondria required for the formation of mitochondrial respiratory chain (MRC) supercomplexes. The destabilization of MRC supercomplexes is the proximal cause of the pathology associated with the depletion of CL in patients with Barth syndrome. Thus, promoting supercomplex formation could ameliorate mitochondrial dysfunction associated with CL depletion. However, to date, physiologically relevant small-molecule regulators of supercomplex formation have not been identified. Here, we report that ethanolamine (Etn) supplementation rescues the MRC defects by promoting supercomplex assembly in a yeast model of Barth syndrome. We discovered this novel role of Etn while testing the hypothesis that elevating mitochondrial phosphatidylethanolamine (PE), a phospholipid suggested to overlap in function with CL, could compensate for CL deficiency. We found that the Etn supplementation rescues the respiratory growth of CL-deficient Saccharomyces cerevisiae cells in a dose-dependent manner but independently of its incorporation into PE. The rescue was specifically dependent on Etn but not choline or serine, the other phospholipid precursors. Etn improved mitochondrial function by restoring the expression of MRC proteins and promoting supercomplex assembly in CL-deficient cells. Consistent with this mechanism, overexpression of Cox4, the MRC complex IV subunit, was sufficient to promote supercomplex formation in CL-deficient cells. Taken together, our work identifies a novel role of a ubiquitous metabolite, Etn, in attenuating mitochondrial dysfunction caused by CL deficiency.

A novel homozygous SLC25A1 mutation with impaired mitochondrial complex V: Possible phenotypic expansion.

SLC25A1 mutations are associated with combined D,L-2-hydroxyglutaric aciduria (DL- 2HGA; OMIM #615182), characterized by muscular hypotonia, severe neurodevelopmental dysfunction and intractable seizures. SLC25A1 encodes the mitochondrial citrate carrier (CIC), which mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Only a single family with an SLC25A1 mutation has been described in which mitochondrial respiratory chain dysfunction was documented, specifically in complex IV. Five infants of two consanguineous Bedouin families of the same tribe presented with small head circumference and neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development culminating in early death. Ventricular septal defects (VSD) were demonstrated in three patients. Blood and CSF lactate were elevated with normal levels of plasma amino acids and free carnitine and increased 2-OH-glutaric acid urinary exertion. EEG was compatible with white matter disorder. Brain MRI revealed ventriculomegaly, thin corpus callosum with increased lactate peak on spectroscopy. Mitochondrial complex V deficiency was demonstrated in skeletal muscle biopsy of one infant. Homozygosity mapping and sequencing ruled out homozygosity of affected individuals in all known complex V-associated genes. Whole exome sequencing identified a novel homozygous SLC25A1 c.713A>G (p.Asn238Ser) mutation, segregating as expected in the affected kindred and not found in 220 control alleles. Thus, SLC25A1 mutations might be associated with mitochondrial complex V deficiency and should be considered in the differential diagnosis of mitochondrial respiratory chain defects.

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies

Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals’ samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp−/− mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp−/− MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.

Mitochondrial respiratory chain defects in autism and other neurodevelopmental disorders

Mitochondrial respiratory electron transport chain (ETC) consists of five multi-subunit enzymes, i.e., complex I-V, which differs not only in structure but also in function, and plays an important role in adenosine triphosphate (ATP) generation by mitochondria. Each of these complexes participates in the generation of proton gradient in the mitochondrial intermembrane space, which is necessary for converting adenosine diphosphate (ADP) into ATP by ATP synthase. Brain has a high demand for energy, and neurons generate energy in the form of ATP through the respiratory chain in the mitochondria. Almost 90% of this energy is provided by mitochondrial ETC. ETC also generates most of the endogenous free radicals, i.e., reactive oxygen species (ROS) of the cell. The normal functions of ETC are essential to maintain physiological function and plasticity of neurons. Therefore, abnormalities in ETC during development, i.e., in utero, infancy and childhood, may be involved in the etiology of neurodevelopmental disorders. The abnormalities in mitochondrial ETC pertaining to neurodevelopmental disorders include mtDNA mutations, altered gene expression, decreased activities and protein expression levels of ETC complexes, and oxidative stress. Here, we review these mitochondrial ETC defects in autism spectrum disorders (ASDs) and other neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder, schizophrenia, Down syndrome and Fragile X syndrome.

Mitochondrial respiratory chain defects in autism and other neurodevelopmental disorders

Mitochondrial respiratory electron transport chain (ETC) consists of five multi-subunit enzymes, i.e., complex I-V, which differs not only in structure but also in function, and plays an important role in adenosine triphosphate (ATP) generation by mitochondria. Each of these complexes participates in the generation of proton gradient in the mitochondrial intermembrane space, which is necessary for converting adenosine diphosphate (ADP) into ATP by ATP synthase. Brain has a high demand for energy, and neurons generate energy in the form of ATP through the respiratory chain in the mitochondria. Almost 90% of this energy is provided by mitochondrial ETC. ETC also generates most of the endogenous free radicals, i.e., reactive oxygen species (ROS) of the cell. The normal functions of ETC are essential to maintain physiological function and plasticity of neurons. Therefore, abnormalities in ETC during development, i.e., in utero, infancy and childhood, may be involved in the etiology of neurodevelopmental disorders. The abnormalities in mitochondrial ETC pertaining to neurodevelopmental disorders include mtDNA mutations, altered gene expression, decreased activities and protein expression levels of ETC complexes, and oxidative stress. Here, we review these mitochondrial ETC defects in autism spectrum disorders (ASDs) and other neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder, schizophrenia, Down syndrome and Fragile X syndrome.