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  • The definition of mitochondrial diseases used in this chapter defines these diseases as conditions in which a defect of the mitochondrial oxidative phosphorylation (OXPHOS) pathway is a key contributor to the pathophysiology of the disease. Classifying which genes fall under that definition remains debatable for some genes where the pathophysiology is not yet completely understood.

  • The mitochondrial OXPHOS pathway consists of five heteropolymeric enzyme complexes in the mitochondrial inner membrane, containing more than 80 different proteins, plus the two electron carriers ubiquinone and cytochrome c. OXPHOS complexes can be further assembled into supercomplexes. A functional OXPHOS pathway relies on the interaction of two genomes. The mitochondrial DNA (mtDNA) encodes 13 of the OXPHOS proteins plus 2 rRNAs and 22 tRNAs required for translation of the mtDNA genome. The nuclear genome encodes hundreds of proteins essential for OXPHOS function. These include subunits and assembly factors for each complex plus all the machinery required for import, processing and quality control of mitochondrial proteins, replication and expression of mtDNA as well as synthesis of redox centers, electron carriers, cofactors, nucleotides and maintaining an appropriate membrane milieu for stability of the OXPHOS complexes. Given this genetic complexity, it is not surprising that mitochondrial diseases are now known to comprise at least 200 monogenic diseases.

  • Mitochondrial diseases encompass a very large number of conditions with a huge clinical spectrum, with signs affecting any tissue in the body, with onset at any age, and with any type of inheritance. The functional, structural and genetic complexity of OXPHOS directly explains the wide diversity of mitochondrial diseases. In most cell types, in particular neuronal and muscle cells, OXPHOS is producing more than 90% of the cellular ATP. In parallel it has central roles in the maintenance of the cellular redox potential, inner membrane potential and reactive oxygen species metabolism.

  • Many mitochondrial diseases are multisystemic, involving several tissues unrelated by functional or embryological link. However tissue-specificity is also frequent and the pathophysiological mechanisms remain largely hypothetical. In mitochondrial diseases affecting a single tissue, demonstration of the mitochondrial defect can be difficult because most histological and enzymatic analyses are made in muscle, which may be spared by the disease. In addition a mitochondrial defect, even severe but affecting a tissue with minor mass, will have little influence on the global metabolic status that is analysed in blood and urine samples.

  • The initial steps in investigating possible mitochondrial disease involve assessment of family history and clinical features, with a focus on recognizing classical mitochondrial syndromes and multisystem disease, together with consideration of possible alternative diagnoses. In most cases, the next steps involve non-invasive studies on body fluids to detect any alteration in cellular redox ratio or accumulation of substrates upstream of the deficient metabolic step, such as lactate, pyruvate or intermediates of the Krebs cycle. Together with imaging, these investigations can guide whether specific single gene tests, gene panels or whole exome sequencing should be performed or if the patient should proceed ...

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