A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia

NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the 'supernumerary' group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in in the X-linked nuclear encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11 but all are associated to a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects

Novel TOP3A Variant Associated With Mitochondrial Disease: Expanding the Clinical Spectrum of Topoisomerase III Alpha-Related Diseases

ObjectivesTopoisomerase III alpha plays a key role in the dissolution of double Holliday junctions and is required for mitochondrial DNA (mtDNA) replication and maintenance. Sequence variants in the TOP3A gene have been associated with the Bloom syndrome-like disorder and described in an adult patient with progressive external ophthalmoplegia. The purpose of this report is to expand the clinical phenotype of the TOP3A-related diseases and clarify the role of this gene in primary mitochondrial disorders.MethodsA 44-year-old woman was referred to our hospital because of exercise intolerance and creatine kinase increase. Muscle biopsy and a targeted next-generation sequencing (NGS) analysis were performed.ResultsA histopathologic assessment documented a mitochondrial myopathy, and a molecular analysis revealed a novel homozygous variant in the TOP3A gene associated with multiple mtDNA deletions.DiscussionThis case suggests that TOP3A is one of the several nuclear genes associated with mtDNA maintenance disorder and expands the spectrum of its associated phenotypes, ranging from a clinical condition defined Bloom syndrome-like disorder to canonical mitochondrial syndromes

Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation

Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next-generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis, and western blot analysis. All patients displayed novel homozygous mutations in the NDUFA12 gene, leading to the virtual absence of the corresponding protein. Surprisingly, despite the fact that in none of the analyzed patients, NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect

Mitochondrial diseases part I: Mouse models of OXPHOS deficiencies caused by defects in respiratory complex subunits or assembly factors

Mitochondrial disorders are the most common inborn errors of metabolism affecting the oxidative phosphorylation system (OXPHOS). Because of the poor knowledge of the pathogenic mechanisms, a cure for these disorders is still unavailable and all the treatments currently in use are supportive more than curative. Therefore, in the past decade a great variety of mouse models have been developed to assess the in vivo function of several mitochondrial proteins involved in human diseases. Due to the genetic and physiological similarity to humans, mice represent reliable models to study the pathogenic mechanisms of mitochondrial disorders and are precious to test new therapeutic approaches. Here we summarize the features of several mouse models of mitochondrial diseases directly related to defects in subunits of the OXPHOS complexes or in assembly factors. We discuss how these models recapitulate many human conditions and how they have contributed to the understanding of mitochondrial function in health and disease

Mouse models of oxidative phosphorylation dysfunction and disease

Oxidative phosphorylation (OXPHOS) deficiency results in a number of human diseases, affecting at least one in 5000 of the general population. Altering the function of genes by mutations are central to our understanding their function. Prior to the development of gene targeting, this approach was limited to rare spontaneous mutations that resulted in a phenotype. Since its discovery, targeted mutagenesis of the mouse germline has proved to be a powerful approach to understand the in vivo function of genes. Gene targeting has yielded remarkable understanding of the role of several gene products in the OXPHOS system. We provide a “tool box” of mouse models with OXPHOS defects that could be used to answer diverse scientific questions

Mitochondrial Diseases Part III: Therapeutic interventions in mouse models of OXPHOS deficiencies

Mitochondrial defects are the cause of numerous disorders affecting the oxidative phosphorylation system (OXPHOS) in humans leading predominantly to neurological and muscular degeneration. The molecular origin, manifestations, and progression of mitochondrial diseases have a broad spectrum, which makes very challenging to find a globally effective therapy. The study of the molecular mechanisms underlying the mitochondrial dysfunction indicates that there is a wide range of pathways, enzymes and molecules that can be potentially targeted for therapeutic purposes. Therefore, focusing on the pathology of the disease is essential to design new treatments. In this review, we will summarize and discuss the different therapeutic interventions tested in some mouse models of mitochondrial diseases emphasizing the molecular mechanisms of action and their potential applications

Mitochondrial Diseases Part II: Mouse models of OXPHOS deficiencies caused by defects in regulatory factors and other components required for mitochondrial function

Mitochondrial disorders are defined as defects that affect the oxidative phosphorylation system (OXPHOS). They are characterized by a heterogeneous array of clinical presentations due in part to a wide variety of factors required for proper function of the components of the OXPHOS system. There is no cure for these disorders owing to our poor knowledge of the pathogenic mechanisms of disease. To understand the mechanisms of human disease numerous mouse models have been developed in recent years. Here we summarize the features of several mouse models of mitochondrial diseases directly related to those factors affecting mtDNA maintenance, replication, transcription, translation as well as other proteins that are involved in mitochondrial dynamics and quality control which affect mitochondrial OXPHOS function without being intrinsic components of the system. We discuss how these models have contributed to our understanding of mitochondrial diseases and their pathogenic mechanisms

mTERF2 regulates oxidative phosphorylation by modulating mtDNA transcription

Regulation of mitochondrial protein expression is crucial for the function of the oxidative phosphorylation (OXPHOS) system. Although the basal machinery for mitochondrial transcription is known, the regulatory mechanisms are not completely understood. Here, we characterized mTERF2, a mitochondria-localized homolog of the mitochondrial transcription termination factor mTERF1. We show that inactivation of mTERF2 in the mouse results in a myopathy and memory deficits associated with decreased levels of mitochondrial transcripts and imbalanced tRNA pool. These aberrations were associated with decreased steady-state levels of OXPHOS proteins causing a decrease in respiratory function. mTERF2 binds to the mtDNA promoter region, suggesting that it affects transcription initiation. In vitro interaction studies suggest that mtDNA mediates interactions between mTERF2 and mTERF3. Our results indicate that mTERF1, mTERF2, and mTERF3 regulate transcription by acting in the same site in the mtDNA promoter region and thereby mediate fine-tuning of mitochondrial transcription and hence OXPHOS function

Mouse models of oxidative phosphorylation defects: Powerful tools to study the pathobiology of mitochondrial diseases

Defects in the oxidative phosphorylation system (OXPHOS) are responsible for a group of extremely heterogeneous and pleiotropic pathologies commonly known as mitochondrial diseases. Although many mutations have been found to be responsible for OXPHOS defects, their pathogenetic mechanisms are still poorly understood. An important contribution to investigate the in vivo function of several mitochondrial proteins and their role in mitochondrial dysfunction, has been provided by mouse models. Thanks to their genetic and physiologic similarity to humans, mouse models represent a powerful tool to investigate the impact of pathological mutations on metabolic pathways. In this review we discuss the main mouse models of mitochondrial disease developed, focusing on the ones that directly affect the OXPHOS system