Mitochondrial Neurodegeneration

Abstract

Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA found in mitochondria themselves, and are termed mitochondrial DNA (mtDNA). Mutations striking either genome can lead to mitochondrial impairment, determining infantile, childhood or adult neurodegeneration. Mitochondrial disorders are complex neurological syndromes, and are often part of a multisystem disorder. In this paper, we divide the diseases into those caused by mtDNA defects and those that are due to mutations involving nuclear genes; from a clinical point of view, we discuss pediatric disorders in comparison to juvenile or adult-onset conditions. The complementary genetic contributions controlling organellar function and the complexity of the biochemical pathways present in the mitochondria justify the extreme genetic and phenotypic heterogeneity of this new area of inborn errors of metabolism known as 'mitochondrial medicine'.

Keywords: Leigh syndrome; MELAS; MERRF; OXPHOS; POLG; mitochondrial disease; mitochondrial respiratory chain.

Figure 1

Genetic classification of OXPHOS disease mutations. On the upper right, a scheme of human mtDNA is depicted. The two ribosomal RNA genes are in dark yellow. CI genes are in blue; the CIII gene is in green; the CIV genes are in light yellow; and the CV genes are in red. The non-coding region (NCR) is in beige. The tRNA genes are represented by circles and designated according to the single-letter code of the corresponding amino acid. On the bottom right, a pie chart summarizes the current knowledge about the human mitochondrial proteome. Different colors indicate different categories of proteins. Adapted from [12] under the Creative Commons Attribution license.

Figure 2

Neuropathology in Leigh disease. (A) necrotizing lesions in the medulla oblongata (H&E) and (B) mesencephalon (autoptic specimen). (C) H&E staining showing neuronal loss, microcystic cavitation of the neuropilum, vessel proliferation, and microgliosis; (D) GFAP immunohistochemistry shows marked gliosis in the dentate nucleus. Adapted and modified from: [114].

Figure 3

Neuroimaging in Leigh disease. (A,B) Magnetic resonance imaging (MRI) of patient presenting with Leigh phenotype with complex I deficiency due to m.10158T>C mutation in MTND3 gene: coronal (A) and axial (B) T2-weighted images show bilateral putaminal hyperintense lesions and minimal posterior periventricular white matter hyperintensity (B). (C,D) MRI of patient presenting with mitochondrial leukoencephalopathy with complex II deficiency due to mutation p.Gly169Cys of SDHAF1 gene: coronal (C) and axial (D) T2-weighted images show hyperintensity of the lobar white matter also involving the corpus callosum and the posterior arms of the internal capsule (D); the white matter is abnormal also in the cerebellar hemispheres (C). Adapted from: [115].

Figure 4

A patient affected with Alpers–Huttenlocher (AHS) diseases. (A,B) Head MRI scan (coronal plane, T2 weighed images). Bilateral focal hyperintensities are seen of the hemispheric cortex and thalami (A), of the white matter and cerebellar cortex (B). (C–F) Histological sections through cortical lesions of the same patient (HE stain; C, E, F, and GFAP; D). The pattern of the necrotizing lesions of the cortex is shown with microcavitation, vessel proliferation, neuronal loss (C), and the associated gliosis (D). Features of cell death: acute ischemic changes (arrow; E) and nuclear fragmentation (arrowhead; F) of two cortical neurons. Adapted from [132].

Figure 5

Neuropathology of the cervical spinal cord in a case of juvenile AHS. Both dorsal tracts, which carry deep sensation, are weakly stained (asterisk on the right one) and show intense gliosis (inset). Woelcke modified stain for myelin and GFAP immunohistochemistry (inset). Adapted from [114].

Figure 6

Clinical variability of diseases caused by ARSs mutations. (A) Tissues commonly affected by mutations in cytosolic, bifunctional, and mitochondrial ARS genes. (B) Common neurological presentations reported in cytosolic, bifunctional, and mitochondrial ARS genes, with peripheral neuropathy highlighted. The solid line indicates a dominant mode of inheritance, the dashed line indicates the recessive mode of inheritance. Adapted and modified from [153].

Figure 7

Brain MRI of a patient with KSS. An 18-year-old woman. T2-weighted transverse (A) and coronal (B) images show abnormal signals in the white matter of the centrum semiovale, especially in the perirolandic region and subcortical areas, and in the mesencephalon. From: [114].

Figure 8

Brain MRI of a MELAS case, a 14-year-old girl. Sagittal T1-weighted section (A) of the left cerebral hemisphere shows a vast posterior lesion. A proton-density coronal section (B) shows, in addition to the temporo-occipital lesion, bilateral lesions, and atrophy of the cerebellar cortex. Serial CT scan examinations (C–E) show a reduction of the left temporal-occipital lesion (from C to D) but the appearance of a new lesion in the right temporo-occipital region (D). Two years later, there is marked bilateral atrophy of the posterior cerebral region (E). As is frequently observed in MELAS patients, as well as in other mitochondrial disorders, calcium deposits are detected in the left putamen (C,E). Adapted from [114].

Figure 9

Brain MRI in SCAE. (A) Occipital pole lesion; (B) multiple lesions in cerebral cortical, subcortical, and thalamic areas; (C) bilateral lesions in the central cerebellar white matter. Adapted from [114].