Mitochondrial disorders of the OXPHOS system

Cytochrome-c-oxidase (COX) subunit 4 (COX4) plays important roles in the function, assembly and regulation of COX (mitochondrial respiratory complex 4), the terminal electron acceptor of the oxidative phosphorylation (OXPHOS) system. The principal COX4 isoform, COX4-1, is expressed in all tissues, whereas COX4-2 is mainly expressed in the lungs, or under hypoxia and other stress conditions. We have previously described a patient with a COX4-1 defect with a relatively mild presentation compared to other primary COX deficiencies, and hypothesized that this could be the result of a compensatory upregulation of COX4-2. To this end, COX4-1 was downregulated by shRNAs in human foreskin fibroblasts (HFF) and compared to the patient’s cells. COX4-1, COX4-2 and HIF-1α were detected by immunocytochemistry. The mRNA transcripts of both COX4 isoforms and HIF-1 target genes were quantified by RT-qPCR. COX activity and OXPHOS function were measured by enzymatic and oxygen consumption assays, respectively. Pathways were analyzed by CEL-Seq2 and by RT-qPCR. We demonstrated elevated COX4-2 levels in the COX4-1-deficient cells, with a concomitant HIF-1α stabilization, nuclear localization and upregulation of the hypoxia and glycolysis pathways. We suggest that COX4-2 and HIF-1α are upregulated also in normoxia as a compensatory mechanism in COX4-1 deficiency.

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Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22158325 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8325

Author(s):

Paola Zanfardino ◽

Stefano Doccini ◽

Filippo M. Santorelli ◽

Vittoria Petruzzella

Keyword(s):

Human Brain ◽

Basic Function ◽

Mitochondrial Proteome ◽

Novel Proteins ◽

Mitochondrial Functions ◽

Organ Specific ◽

Oxphos System ◽

Mitochondrial Defects ◽

Energy Dependent ◽

The Brain

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as ‘mitoexome’, ‘mitoproteome’ and ‘mitointeractome’ have entered the field of ‘mitochondrial medicine’. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.

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Genomic sequencing for the diagnosis of childhood mitochondrial disorders: a health economic evaluation

European Journal of Human Genetics ◽

10.1038/s41431-021-00916-8 ◽

2021 ◽

Author(s):

You Wu ◽

Shanti Balasubramaniam ◽

Rocio Rius ◽

David R. Thorburn ◽

John Christodoulou ◽

...

Keyword(s):

Health Economic ◽

Economic Evaluation ◽

Health Economic Evaluation ◽

Mitochondrial Disorders ◽

Genomic Sequencing

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Serum biomarkers in primary mitochondrial disorders

Brain Communications ◽

10.1093/braincomms/fcaa222 ◽

2021 ◽

Author(s):

Kristin N Varhaug ◽

Omar Hikmat ◽

Hanne Linda Nakkestad ◽

Christian A Vedeler ◽

Laurence A Bindoff

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Mitochondrial Disease ◽

Central Nervous System Involvement ◽

Mitochondrial Disorders ◽

Serum Biomarkers ◽

Fibroblast Growth Factor 21 ◽

Enzyme Linked Immunosorbent Assay ◽

Mitochondrial Dna Deletion ◽

Muscle Involvement

Abstract The aim of this study was to explore the utility of the serum biomarkers neurofilament light chain (NF-L), fibroblast growth factor 21 (FGF-21) and growth and differentiation factor 15 (GDF-15) in diagnosing primary mitochondrial disorders. We measured serum NF-L, FGF-21 and GDF-15 in 26 patients with a genetically proven mitochondrial disease. FGF-21 and GDF-15 were measured by enzyme-linked immunosorbent assay and NF-L with the Simoa assay. NF-L was highest in patients with multisystemic involvement that included the central nervous system such as those with the m.3242A>G mutation. Mean NF-L was also highest in patients with epilepsy versus those without (49.74 pg/ml versus 19.7 pg/ml (p = 0.015)), while FGF-21 and GDF-15 levels were highest in patients with prominent myopathy, such as those with single mitochondrial DNA deletion. Our results suggest that the combination of NF-L, FGF-21 and GDF-15 is useful in the diagnostic evaluation of mitochondrial disease. GDF-15 and FGF-21 identify those with muscle involvement while NF-L is a clear marker for central nervous system involvement independent of underlying mitochondrial pathology. Levels of NF-L appear to correlate with the degree of ongoing damage suggesting, therefore, that monitoring NF-L levels may provide prognostic information and a way of monitoring disease activity.

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Mitochondrial Syndromes Revisited

Journal of Clinical Medicine ◽

10.3390/jcm10061249 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1249

Author(s):

Daniele Orsucci ◽

Elena Caldarazzo Ienco ◽

Andrea Rossi ◽

Gabriele Siciliano ◽

Michelangelo Mancuso

Keyword(s):

Clinical Trials ◽

Genetic Basis ◽

Phenotypic Variability ◽

Mitochondrial Diseases ◽

Genetic Alterations ◽

Mitochondrial Disorders ◽

Single Mutation ◽

Multicenter Studies ◽

Future Studies ◽

Clinical Syndromes

In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to mitochondrial disorders and the peculiar characteristics of their genetics make mitochondrial disorders a complex group of disorders. Although specific genetic alterations have been associated with some syndromic presentations, the genotype–phenotype relationship in mitochondrial disorders is complex (a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes). This review will revisit the most common syndromic pictures of mitochondrial disorders, from a clinical rather than a molecular perspective. We believe that the new phenotype definitions implemented by recent large multicenter studies, and revised here, may contribute to a more homogeneous patient categorization, which will be useful in future studies on natural history and clinical trials.

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