**4. Diseases caused by mutations in genes that encode subunits of the respiratory chain**

The most frequent of these diseases are those that code for subunits of complexes I and II and cause Leigh's syndrome, which is a fatal neurodegenerative disease that begins in the first years of life due to a profound defect in the production of ATP in the developing brain. It is defined by the presence of bilateral necrotic lesions in ganglia of the base and brain stem, characterized histologically by cavitated areas, vascular proliferation, neuronal loss, and demyelination. Individuals with Leigh's syndrome can also present variable symptoms that do not fit into any defined syndrome (hypotonia, cardiomyopathy, ataxia, developmental delay, etc.) [70]. The most important genes that code for complex I subunits are NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS8, NDUFV1, and NDUFV2 [71–73].

#### **4.1. Diseases caused by mutations in genes that code for anchor proteins**

This group of diseases includes mutations in genes that code for proteins that, while not part of the mitochondrial respiratory chain, are necessary for the correct assembly of proteins encoded by the nuclear and the mitochondrial genomes. Examples are mutations in the nuclear SURF1, LRPPRC, and NDUFA12L genes, which code for proteins necessary for the assembly of cyclooxygenase (COX) [73, 74].

Primary deficits of coenzyme Q10 (CoQ10) include various disorders caused by defects of their biosynthesis at different levels. The CoQ10 transports electrons from complexes I and II to complex III and receives electrons from the beta-oxidation pathway via electron-transferringflavoprotein dehydrogenase (ETFDH) [75]. There are at least nine enzymes necessary for the synthesis of CoQ10, and mutations in the genes that encode them are responsible for different cases of encephalomyopathies. There are also disorders due to CoQ10 secondary deficits, including autosomal recessive cases of cerebellar ataxia of unknown cause in children, apraxia syndrome with oculomotor ataxia 2 (AOA2) caused by mutations in the aprataxin gene (APTX), and myopathic form of glutaric aciduria type II (GAII) caused by mutations in the gene that encodes the ETFDH [76, 77]. The importance of knowledge of these disorders is that supplements with CoQ10 improve the symptoms in these patients. Defects have also been described in proteins involved in the assembly of complex III (BCS1L) and complex V (ATPAF2) [3, 74].

## **4.2. Diseases secondary to defects in intergenomic communication**

oxidative phosphorylation (OXPHOS) system because for many years only mutations in mtDNA related to these diseases had been detected. But, identification of nuclear genes encoding proteins of the OXPHOS system complexes, or responsible for their assembly, has been described [68].

Mitochondrial disease can associate with any symptom, in any organ, at any age, but some symptoms and signs are actually more suggestive of a mitochondrial disorder than others. These "warning signs" warrant the onset of a diagnostic assessment of mitochondrial diseases. In contrast, numerous nonspecific symptoms occur frequently in infants and children with mitochondrial disease, but they have a broad differential diagnosis and lead more often to other diagnoses [68]. For example, pigmentary retinopathy in a preadolescent child may be a trait of mitochondrial disease but should suggest the possibility of juvenile neuronal ceroid lipofuscinosis or another genetic syndrome. Thus, nonspecific symptoms, especially isolated ones, do not indicate per se a mitochondrial problem. However, when combined, the likelihood of mitochondrial disorder increases, especially if the nonspecific aspects affect different organ systems, which leads to the initiation of appropriate initial diagnostic investigations [53, 69]. The defects of the respiratory chain of Mendelian inheritance are included in four groups:

**4.** Defects that affect the constituent lipids of the inner mitochondrial membrane where CR

The most frequent of these diseases are those that code for subunits of complexes I and II and cause Leigh's syndrome, which is a fatal neurodegenerative disease that begins in the first years of life due to a profound defect in the production of ATP in the developing brain. It is defined by the presence of bilateral necrotic lesions in ganglia of the base and brain stem, characterized histologically by cavitated areas, vascular proliferation, neuronal loss, and demyelination. Individuals with Leigh's syndrome can also present variable symptoms that do not fit into any defined syndrome (hypotonia, cardiomyopathy, ataxia, developmental delay, etc.) [70]. The most important genes that code for complex I subunits are NDUFS1,

This group of diseases includes mutations in genes that code for proteins that, while not part of the mitochondrial respiratory chain, are necessary for the correct assembly of proteins encoded by the nuclear and the mitochondrial genomes. Examples are mutations in the nuclear SURF1, LRPPRC, and NDUFA12L genes, which code for proteins necessary for the

**4. Diseases caused by mutations in genes that encode subunits of the** 

NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS8, NDUFV1, and NDUFV2 [71–73].

**4.1. Diseases caused by mutations in genes that code for anchor proteins**

**1.** Mutations in genes that code for subunits of the respiratory chain

**2.** Mutations in genes that code for anchor proteins

**3.** Defects in intergenomic communication

assembly of cyclooxygenase (COX) [73, 74].

is embedded

166 Mitochondrial DNA - New Insights

**respiratory chain**

These diseases are due to defects in nuclear factors involved in the replication, maintenance, and translation of mtDNA. The resulting disorders are characterized by quantitative alterations (depletion syndromes) or qualitative alterations (multiple deletions) of mtDNA or by defects in the translation of respiratory chain components encoded in the mtDNA. Thus, many of these disorders are due to alterations in the pool of nucleotides necessary for the synthesis of mtDNA or in the enzymes necessary for the replication of mtDNA itself [78, 79].

**Figure 8.** Multiple deletions of mtDNA. Mitochondrial damage is regulated by multiple deletions in the PEO, ANT1, ECGF I, POLG, and OLG2 genes. The deletions will trigger the syndromes and signs that are illustrated in the image. This image is a modification of QIAGEN's original [Torres-Sánchez ED].
