Oxidative Phosphorylation Deficiency Research Articles

Adult-Onset Deficiency of Mitochondrial Complex III in a Mouse Model of Alzheimer's Disease Decreases Amyloid Beta Plaque Formation.

For decades, mitochondrial dysfunctions and the generation of reactive oxygen species have been proposed to promote the development and progression of the amyloid pathology in Alzheimer's disease, but this association is still debated. It is unclear whether different mitochondrial dysfunctions, such as oxidative phosphorylation deficiency and oxidative stress, are triggers or rather consequences of the formation of amyloid aggregates. Likewise, the role of the different mitochondrial oxidative phosphorylation complexes in Alzheimer's patients' brain remains poorly understood. Previous studies showed that genetic ablation of oxidative phosphorylation enzymes from early age decreased amyloid pathology, which were unexpected results. To better model oxidative phosphorylation defects in aging, we induced the ablation of mitochondrial Complex III (CIIIKO) in forebrain neurons of adult mice with amyloid pathology. We found that mitochondrial Complex III dysfunction in adult neurons induced mild oxidative stress but did not increase amyloid beta accumulation. On the contrary, CIIIKO-AD mice showed decreased plaque number, decreased Aβ42 toxic fragment, and altered amyloid precursor protein clearance pathway. Our results support the hypothesis that mitochondrial dysfunctions alone, caused by oxidative phosphorylation deficiency, is not the cause of amyloid accumulation.

Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion.

Patients with dermatomyositis (DM) suffer from reduced aerobic metabolism contributing to impaired muscle function, which has been linked to cytochrome c oxidase (COX) deficiency in muscle tissue. This mitochondrial respiratory chain dysfunction is typically seen in perifascicular regions, which also show the most intense inflammatory reaction along with capillary loss and muscle fibre atrophy. The objective of this study was to investigate the pathobiology of the oxidative phosphorylation deficiency in DM. Muscle biopsy specimens with perifascicular COX deficiency from five juveniles and seven adults with DM were investigated. We combined immunohistochemical analyses of subunits in the respiratory chain including complex I (subunit NDUFB8), complex II (succinate dehydrogenase, subunit SDHB) and complex IV (COX, subunit MTCO1) with in situ hybridisation, next generation deep sequencing and quantitative polymerase chain reaction (PCR). There was a profound deficiency of complexes I and IV in the perifascicular regions with enzyme histochemical COX deficiency, whereas succinate dehydrogenase activity and complex II were preserved. In situ hybridisation of mitochondrial RNA showed depletion of mitochondrial DNA (mtDNA) transcripts in the perifascicular regions. Analysis of mtDNA by next generation deep sequencing and quantitative PCR in affected muscle regions showed an overall reduction of mtDNA copy number particularly in the perifascicular regions. The respiratory chain dysfunction in DM muscle is associated with mtDNA depletion causing deficiency of complexes I and IV, which are partially encoded by mtDNA, whereas complex II, which is entirely encoded by nuclear DNA, is preserved. The depletion of mtDNA indicates a perturbed replication of mtDNA explaining the muscle pathology and the disturbed aerobic metabolism.

Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family.

Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.

La Esclerosis lateral amiotrófica no es solo una enfermedad de la motoneurona: impacto del eje simpatoadrenal

Amyotrophic lateral sclerosis (ALS), an adult onset, fatal neurodegenerative disease, has as a cardinal pathogenic feature the selective death of motor neurons (MNs) at the cortex, brainstem, and spinal cord. In this review we focus on four aspects: (i) the hypothesis of disease propagation through the cerebrospinal fluid (CSF); (ii) the distortion of the exocytotic release of neurotransmitters at the sympathoadrenal axis; (iii) the ultrastructural and functional alterations of mitochondria from adrenal medullary chromaffin cells (CCs); and (iv) the purinergic P2X7 receptor (P2X7R) as a potential target for neuroprotection. Concerning disease propagation from one to another area of the central nervous system (CNS), the pattern of clinical progression suggests that the disease spreads centrifugally. This indicates that a kind of toxin agent may be released and propagated through the CSF. In our laboratory we found that CSF from ALS patients exerted toxic effects on cultured cortical MNs. In CCs, we found deep distortions of the exocytotic kinetics and the exocytotic fusion pore in the process of catecholamine release, in the SOD1G93A mouse model of ALS. Furthermore, we found that these alterations could be related to the accumulation of mutated SOD1 into mitochondria; this resulted in mitochondrial depolarization, excess production of reactive oxygen species and deficiency in oxidative phosphorylation. Finally, we discuss recent data on the potential therapeutic effect of compound JNJ-47965567, a blocker of P2X7Rs known to be central-stage in neuroinflammation. Upon its chronic administration to SOD1G93A, we found that the compound delayed disease onset but only in females mice. In conclusion, why MN selectively die in ALS disease, remains a mystery; On the other hand, it seems that other cell types are also affected, particularly at the sympathoadrenal axis. As disease pathogenesis remains obscure, the search of therapeutic targets to slow disease progression in ALS, remains puzzling.

Study of novel NARS2 variants in patient of combined oxidative phosphorylation deficiency 24.

NARS2 catalyzes the attachment of asparagine amino acids to mitochondrial tRNAAsn and is critical for efficient mitochondrial protein synthesis. Biallelic variants in NARS2 are associated with combined oxidative phosphorylation deficiency 24 (COXPD24) and autosomal recessive deafness-94. Patient information was obtained after recruitment. Genetic tests were performed using whole exome sequencing (WES) and Sanger sequencing. Structure prediction was based on the RaptorX and SWISS-MODEL platforms. The mRNA analysis of paternal variant was performed. Expression levels and dimerization of wild-type (WT) and mutant NARS2 were detected in human embryonic kidney (HEK) 293T cells. Mitochondrial localization of NARS2 variants was determined using immunofluorescence staining. The patient presented early onset generalized epilepsy, myoclonic seizures, severe bilateral hearing impairment and affected liver and heart. WES identified two compound heterozygous variants in NARS2: c.1141A>G/p.Asn381Asp and c.1290G>C/p.Trp430Cys. In silico analysis predicted that both variants would cause significant and pathogenic changes in secondary structure. NARS2 c.1290G>C is a variant at the first nucleotide of an exon, a location thought to affect mRNA splicing. Although transcriptional experiments did not identify aberrant splicing, we observed a lower proportion of transcripts from the NARS2 c.1290G>C variant. An in vitro experiment showed that both variants impaired NARS2 expression, while mitochondrial localization and dimerization remained unaffected. The patient was diagnosed with COXPD24 caused by novel NARS2 variations. The cardiac dysfunction is identified for the first time. In vitro study revealed impairment of variants on NARS2 expression. These data enrich our knowledge regarding the phenotypic and genotypic spectra of NARS2.

Generation of patient-derived IPSC lines from a girl with Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) caused by compound heterozygous GTPBP3 variants

Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) caused by mutations in GTPBP3 gene is a rare mitochondrial disease. The patient-derived PBMCs of sibling with the compound heterozygous variants in GTPBP3 (NM_133644): c.1289G>A(p.Cys430Tyr); c.545G>A(p.Gly182Glu) were reprogrammed into induced pluripotent stemcell (iPSC) lines (DPNJMUi001-A.) using non-integrative Sendai virus. The COXPD23 iPSC lines present normal karyotypes, high expression of pluripotency markers and the capacity to differentiate into cells of all three germ layers.

Novel Pathogenic Sequence Variation m.5789T>C Causes NARP Syndrome and Promotes Formation of Deletions of the Mitochondrial Genome.

Background and ObjectivesWe report the pathogenic sequence variant m.5789T>C in the anticodon stem of the mitochondrial tRNA for cysteine as a novel cause of neuropathy, ataxia, and retinitis pigmentosa (NARP), which is usually associated with pathogenic variants in the MT-ATP6 gene.MethodsTo address the correlation of oxidative phosphorylation deficiency with mutation loads, we performed genotyping on single laser-dissected skeletal muscle fibers. Stability of the mitochondrial tRNACys was investigated by Northern blotting. Accompanying deletions of the mitochondrial genome were detected by long-range PCR and their breakpoints were determined by sequencing of single-molecule amplicons.ResultsThe sequence variant m.5789T>C, originating from the patient's mother, decreases the stability of the mitochondrial tRNA for cysteine by disrupting the anticodon stem, which subsequently leads to a combined oxidative phosphorylation deficiency. In parallel, we observed a prominent cluster of low-abundance somatic deletions with breakpoints in the immediate vicinity of the m.5789T>C variant. Strikingly, all deletion-carrying mitochondrial DNA (mtDNA) species, in which the corresponding nucleotide position was not removed, harbored the mutant allele, and none carried the wild-type allele.DiscussionIn addition to providing evidence for the novel association of a tRNA sequence alteration with NARP syndrome, our observations support the hypothesis that single nucleotide changes can lead to increased occurrence of site-specific mtDNA deletions through the formation of an imperfect repeat. This finding might be relevant for understanding mechanisms of deletion generation in the human mitochondrial genome.

Complement C1q Binding Protein (C1QBP): Physiological Functions, Mutation-Associated Mitochondrial Cardiomyopathy and Current Disease Models

Complement C1q binding protein (C1QBP, p32) is primarily localized in mitochondrial matrix and associated with mitochondrial oxidative phosphorylative function. C1QBP deficiency presents as a mitochondrial disorder involving multiple organ systems. Recently, disease associated C1QBP mutations have been identified in patients with a combined oxidative phosphorylation deficiency taking an autosomal recessive inherited pattern. The clinical spectrum ranges from intrauterine growth restriction to childhood (cardio) myopathy and late-onset progressive external ophthalmoplegia. This review summarizes the physiological functions of C1QBP, its mutation-associated mitochondrial cardiomyopathy shown in the reported available patients and current experimental disease platforms modeling these conditions.

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.

Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.

Novel heterozygous compound TRMT5 mutations associated with combined oxidative phosphorylation deficiency 26 in a Chinese family: a case report

BackgroundCombined oxidative phosphorylation deficiency 26 (COXPD26) is an autosomal recessive disorder characterized by early onset, developmental delay, gastrointestinal dysfunction, shortness of breath, exercise intolerance, hypotonia and muscle weakness, neuropathy, and spastic diplegia. This disease is considered to be caused by compound heterozygous mutations in the TRMT5 gene.Case presentationIn this study, we report a female child with COXPD26 manifesting as shortness of breath, gastrointestinal dysmotility, severe developmental delay, muscle hypotonia and weakness, exercise intolerance, renal and hepatic defects, and recurrent seizures with spastic diplegia. Interestingly, the hepatic feature was first observed in a COXPD26 patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the TRMT5 gene were detected, which were c.881A>C (p.E294A) from her mother and c.1218G>C (p.Q406H) and c.1481C>T (p.T494M) from her father.ConclusionThe newly emerged clinical features and mutations of this patient provide useful information for further exploration of genotype–phenotype correlations in COXPD26.

FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation.

Background and ObjectivesTo determine common clinical and biological traits in 2 individuals with variants in ISCU and FDX2, displaying severe and recurrent rhabdomyolyses and lactic acidosis.MethodsWe performed a clinical characterization of 2 distinct individuals with biallelic ISCU or FDX2 variants from 2 separate families and a biological characterization with muscle and cells from those patients.ResultsThe individual with FDX2 variants was clinically more affected than the individual with ISCU variants. Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates and mitochondrial complex I and PDHc activities, associated with high levels of blood FGF21. ISCU individual fibroblasts showed no oxidative phosphorylation deficiency and moderate increase of blood FGF21 levels relative to controls. The severity of the FDX2 individual was not due to dysfunctional autophagy. Iron was excessively accumulated in ISCU-deficient skeletal muscle, which was accompanied by a downregulation of IRP1 and mitoferrin2 genes and an upregulation of frataxin (FXN) gene expression. This excessive iron accumulation was absent from FDX2 affected muscle and could not be correlated with variable gene expression in muscle cells.DiscussionWe conclude that FDX2 and ISCU variants result in a similar muscle phenotype, that differ in severity and skeletal muscle iron accumulation. ISCU and FDX2 are not involved in mitochondrial iron influx contrary to frataxin.

Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report

BackgroundMitochondrial ribosomal protein S2 (MRPS2) gene mutation, which is related to severe hypoglycemia and lactic acidosis, is rarely reported globally.Case presentationWe report a case of a new MRPS2 gene mutation in a Chinese girl who presented with hypoglycemia and lactic acidosis. A homozygous C.412C > G variant that could cause complex oxidative phosphorylation deficiency and had not been reported before was identified. The clinical manifestations included recurrent vomiting, hypoglycemia, lactic acidosis, sensorineural hearing loss, and gall bladder calculi. Hypoglycemia and lactic acidosis improved after the administration of sugary liquid and supportive treatments.ConclusionsRecurrent hypoglycemia with lactic acidosis and sensorineural hearing loss should lead to suspicion of mitochondrial defects and the early refinement of genetic tests.

Chlorfenapyr Induce Oxidative Phosphorylation Deficiency in Exposed Rat and the Quinoa Effective Role

Chlorfenapyr Induce Oxidative Phosphorylation Deficiency in Exposed Rat and the Quinoa Effective Role

Складнощі діагностики рідкісної вродженої мітохондріальної патології — комбінованого дефіциту окисного фосфорилювання 26-го типу в дитини раннього віку: клінічний випадок

Hereditary mitochondrial diseases are a consequence of congenital errors in energy metabolism with very variable and predominantly multisystem manifestations, they require differential diagnosis with a wide range of phenotypically similar nosologies, and their verification is a complex problem with a need of a multidisciplinary approach. The article describes a rare clinical case diagnosed in a girl of early age of a congenital mitochondrial pathology with autosomal recessive inheritance — a combined oxidative phosphorylation deficiency of type 26 (COXPD-26) due to two mutations in the heterozygous state of the TRMT5 gene (tRNA methyltransferase 5) on the chromosome 14q23. The patient's illness was accompanied by a debut from birth and was characterized by insufficient weight gain, manifestations of cardiomyopathy, repeated intercurrent infectious diseases with increased activity of blood transaminases, creatine kinase-MB, hepatopathy with hypoalbuminemia, convulsive syndrome, intolerance to valproic acid, progressive delay in stato-kinetic and psychoverbal development, that is, the symptomatology was characterized by progression, multisystem character with predominant damage to the heart, liver and nervous system. The diagnostic algorithm for mitochondrial diseases is one of the most complex in medical practice. In young children, persistent or progressive multisystem disorder of unknown etiology, unknown multiple complex neurological manifestations or neurological monosymptom with involvement of other systems, less often — specific clinical symptoms; persistent lactic acidosis, other positive or questionable laboratory screening findings are suspicious of probable mitochondrial pathology. Numerous hospitalizations, repeated consultations by different specialists, multiple additional labtests, and multiple conflicting diagnoses may indicate a possible mitochondrial pathology. Only whole exome sequencing of a blood sample with an analysis of variations in the number of copies of genes and genomic sequencing of a new generation with targeted genetic testing made it possible to diagnose in a child a hereditary metabolic disorder from the group of defects in the mitochondrial respiratory chain — a combined deficiency of oxidative phosphorylation type 26, previously described in only a few patients. The research was carried out in accordance with the principles of the Helsinki declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: mitochondrial pathology, combined deficiency of oxidative phosphorylation of type 26 (COXPD-26), clinical case.

Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations.

Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a recessive mitochondrial translation disorder caused by mutations in GFM1, a nuclear gene encoding mitochondrial elongation factor G1 (EFG1). Patients with COXPD1 typically present hepatoencephalopathy early after birth with rapid disease progression, and usually die within the first few weeks or years of life. We have generated two different mouse models: a Gfm1knock-in (KI) harboring the p.R671C missense mutation, found in at least 10 patients who survived more than 1year, and a Gfm1knock-out (KO) model. Homozygous KO mice (Gfm1-/- ) were embryonically lethal, whereas homozygous KI (Gfm1R671C/R671C ) mice were viable and showed normal growth. R671C mutation in Gfm1 caused drastic reductions in the mitochondrial EFG1 protein content in different organs. Six- to eight-week-old Gfm1R671C/R671C mice showed partial reductions of in organello mitochondrial translation and respiratory complex IV enzyme activity in the liver. Compound heterozygous Gfm1R671C/- showed a more pronounced decrease of EFG1 protein in liver and brain mitochondria, as compared with Gfm1R671C/R671C mice. At 8weeks of age, their mitochondrial translation rates were significantly reduced in both tissues. Additionally, Gfm1R671C/- mice showed combined oxidative phosphorylation deficiency (reduced complex I and IV enzyme activities in liver and brain), and blue native polyacrylamide gel electrophoresis analysis revealed lower amounts of both affected complexes. We conclude that the compound heterozygous Gfm1R671C/- mouse presents a clear dysfunctional molecular phenotype, showing impaired mitochondrial translation and combined respiratory chain dysfunction, making it a suitable animal model for the study of COXPD1.

Astrocytic Changes in Mitochondrial Oxidative Phosphorylation Protein Levels in Parkinson's Disease

Mitochondrial dysfunction within neurons, particularly those of the substantia nigra, has been well characterized in Parkinson's disease and is considered to be related to the pathogenesis of this disorder. Dysfunction within this important organelle has been suggested to impair neuronal communication and survival; however, the reliance of astrocytes on mitochondria and the impact of their dysfunction on this essential cell type are less well characterized. This study aimed to uncover whether astrocytes harbor oxidative phosphorylation (OXPHOS) deficiencies in Parkinson's disease and whether these deficiencies are more likely to occur in astrocytes closely associated with neurons or those more distant from them. Postmortem human brain sections from patients with Parkinson's disease were subjected to imaging mass cytometry for individual astrocyte analysis of key OXPHOS proteins across all five complexes. We show the variability in the astrocytic expression of mitochondrial proteins between individuals. In addition, we found that there is evidence of deficiencies in respiratory chain subunit expression within these important glia and changes, particularly in mitochondrial mass, associated with Parkinson's disease and that are not simply a consequence of advancing age. Our data show that astrocytes, like neurons, are susceptible to mitochondrial defects and that these could have an impact on their reactivity and ability to support neurons in Parkinson's disease.

High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo.

Mitochondrial transcription factor A (TFAM) is compacting mitochondrial DNA (dmtDNA) into nucleoids and directly controls mtDNA copy number. Here, we show that the TFAM-to-mtDNA ratio is critical for maintaining normal mtDNA expression in different mouse tissues. Moderately increased TFAM protein levels increase mtDNA copy number but a normal TFAM-to-mtDNA ratio is maintained resulting in unaltered mtDNA expression and normal whole animal metabolism. Mice ubiquitously expressing very high TFAM levels develop pathology leading to deficient oxidative phosphorylation (OXPHOS) and early postnatal lethality. The TFAM-to-mtDNA ratio varies widely between tissues in these mice and is very high in skeletal muscle leading to strong repression of mtDNA expression and OXPHOS deficiency. In the heart, increased mtDNA copy number results in a near normal TFAM-to-mtDNA ratio and maintained OXPHOS capacity. In liver, induction of LONP1 protease and mitochondrial RNA polymerase expression counteracts the silencing effect of high TFAM levels. TFAM thus acts as a general repressor of mtDNA expression and this effect can be counterbalanced by tissue-specific expression of regulatory factors.

Machine learning compensates fold-change method and highlights oxidative phosphorylation in the brain transcriptome of Alzheimer\u2019s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder causing 70% of dementia cases. However, the mechanism of disease development is still elusive. Despite the availability of a wide range of biological data, a comprehensive understanding of AD's mechanism from machine learning (ML) is so far unrealized, majorly due to the lack of needed data density. To harness the AD mechanism's knowledge from the expression profiles of postmortem prefrontal cortex samples of 310 AD and 157 controls, we used seven predictive operators or combinations of RapidMiner Studio operators to establish predictive models from the input matrix and to assign a weight to each attribute. Besides, conventional fold-change methods were also applied as controls. The identified genes were further submitted to enrichment analysis for KEGG pathways. The average accuracy of ML models ranges from 86.30% to 91.22%. The overlap ratio of the identified genes between ML and conventional methods ranges from 19.7% to 21.3%. ML exclusively identified oxidative phosphorylation genes in the AD pathway. Our results highlighted the deficiency of oxidative phosphorylation in AD and suggest that ML should be considered as complementary to the conventional fold-change methods in transcriptome studies.

Novel Mutations in the GTPBP3 Gene for Mitochondrial Disease and Characteristics of Related Phenotypic Spectrum: The First Three Cases From China.

Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) caused by mutations in GTPBP3 gene is a rare mitochondrial disease, and this disorder identified from the Chinese population has not been described thus far. Here, we report a case series of three patients with COXPD23 caused by GTPBP3 mutations, from a severe to a mild phenotype. The main clinical features of these patients include lactic acidosis, myocardial damage, and neurologic symptoms. Whole genome sequencing and targeted panels of candidate human mitochondrial genome revealed that patient 1 was a compound heterozygote with novel mutations c.413C > T (p. A138V) and c.509_510del (p. E170Gfs∗42) in GTPBP3. Patient 2 was a compound heterozygote with novel mutations c.544G > T (p. G182X) and c.785A > C (p.Q262P), while patient 3 was a compound heterozygote with a previously reported mutation c.424G > A (p.E142K) and novel mutation c.785A > C (p.Q262P). In conclusion, we first describe three Chinese individuals with COXPD23, and discuss the genotype-phenotype correlations of GTPBP3 mutations. Our findings provide novel information in the diagnosis and genetic counseling of patients with mitochondrial disease.

Mechanisms of the effect of oxidative phosphorylation deficiencies on the skeletal muscle bioenergetic system in patients with mitochondrial myopathies.

Simulations carried out using a previously developed model of the skeletal muscle bioenergetic system, involving the "inorganic phosphate (Pi) double-threshold" mechanism of muscle fatigue, lead to the conclusion that a decrease in the oxidative phosphorylation (OXPHOS) activity, caused by mutations in mitochondrial or nuclear DNA, is the main mechanism underlying the changes in the kinetic properties of the system in mitochondrial myopathies (MM). These changes generally involve the very-heavy-exercise-like behavior and exercise termination because of fatigue at low work intensities. In particular, a sufficiently large (at a given work intensity) decrease in OXPHOS activity leads to slowing of the primary phase II of the oxygen uptake (V̇o2) on-kinetics, decrease in maximal V̇o2 (V̇o2max), appearance of the slow component of the V̇o2 on-kinetics, exercise intolerance, and lactic acidosis at relatively low power outputs encountered in experimental studies in patients with MM. Thus, the "Pi double-threshold" mechanism of muscle fatigue is able to account, at least semiquantitatively, for various kinetic effects of inborn OXPHOS deficiencies of the skeletal muscle bioenergetic system. Exercise can be potentially lengthened and V̇o2max elevated in patients with MM through an increase in peak Pi (Pipeak), at which exercise is terminated because of fatigue. Generally, a mechanism underlying the kinetic effects of OXPHOS deficiencies on the skeletal muscle bioenergetic system in MM is proposed that was absent in the literature.NEW & NOTEWORTHY A mechanism of the OXPHOS deficiencies-induced changes of the skeletal muscle bioenergetic system in patients with mitochondrial myopathies (MM), namely, appearance of the slow component of the V̇o2 on-kinetics at relatively low work intensities, slowed primary phase II of the V̇o2 on-kinetics, lowered V̇o2max, and lactic acidosis is proposed. It involves a decrease in OXPHOS activity acting through the "Pi double-threshold" mechanism of muscle fatigue comprising initiation of the additional ATP usage and termination of exercise.