Mitochondrial disorders

Abstract

In the medical literature the term 'mitochondrial disorders' is to a large extent applied to the clinical syndromes associated with abnormalities of the common final pathway of mitochondrial energy metabolism, i.e. oxidative phosphorylation (OXPHOS). Faulty oxidative phosphorylation may be due to overall dysfunction of the respiratory chain, a heteromultimeric structure embedded in the inner mitochondrial membrane, or can be associated with single or multiple defects of the five complexes forming the respiratory chain itself. From the genetic standpoint, the respiratory chain is a unique structure of the inner mitochondrial membrane formed by means of the complementation of two separate genetic systems: the nuclear genome and the mitochondrial genome. The nuclear genome encodes the large majority of the protein subunits of the respiratory complexes and most of the mitochondrial DNA (mtDNA) replication and expression systems, whereas the mitochondrial genome encodes only 13 respiratory complex subunits, and some RNA components of the mitochondrial translational apparatus. Accordingly, mitochondrial disorders due to defects in OXPHOS include both mendelian-inherited and cytoplasmic-inherited diseases. This review describes human genetic diseases associated with mtDNA and nuclear DNA mutations leading to impaired OXPHOS.

Maternally inherited mitochondrial DNA disease in consanguineous families

“…Mitochondrial disease is genetically and clinically heterogeneous, and can follow mendelian or X-linked inheritance patterns, or be strictly matrilineal in the case of mtDNA mutations; [3][4][5] clinical presentations range from isolated organ involvement (deafness, diabetes and cardiomyopathy) to multisystem, syndromic presentations dominated by muscle and CNS involvement. 6,7 Such heterogeneity can mean that identifying the causative genetic defect is problematic. Given its size, sequencing of the entire mitochondrial genome in clinically affected tissues is often undertaken during the diagnostic work-up unless an autosomal aetiology is suspected, for example, patients born to consanguineous parents or those with affected paternal relatives.…”

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

“…They are mostly caused by mutations in nuclear-or mtDNA-encoded genes of the respiratory chain complexes leading to a variety of clinical manifestations, ranging from lesions in specific tissues, such as in Leber's hereditary optic neuropathy, to complex multisystem syndromes, such as myoclonic epilepsy with ragged-red fibers, Leigh syndrome or the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). 1,2 Despite the detailed knowledge of the molecular defects in these diseases, their pathogenesis remains poorly understood. The heterogeneity of signs and symptoms depends on the diversity of the genetic background and on patient-specific compensatory mechanisms.…”

Mitochondrial DNA mutations in disease and aging

“…There are indeed a large number of different types of mtDNA mutations that have effects on respiratory chain function and ATP synthesis (Larsson and Clayton, 1995;Munnich and Rustin, 2001;Zeviani and Di Donato, 2004). Mutations of mtDNA have several downstream effects that are a consequence of deficient oxidative phosphorylation, and those will be further discussed in the next paragraphs.…”

“…It belongs to the high mobility group domain proteins (Parisi and Clayton, 1991) and can wrap, bend, and compact DNA (Fisher et al, 1992;Kaufman et al, 2007) A large number of pathogenic mtDNA mutations are known, and the reader is referred to specialized reviews on the associated clinical phenotypes (Larsson and Clayton, 1995;Munnich and Rustin, 2001;Zeviani and Di Donato, 2004).…”