Mitochondrial dysfunction in central nervous system white matter disorders

Abstract

Defects of mitochondrial respiration and function had been proposed as a major culprit in the most common neurodegenerative diseases, including prototypic diseases of central nervous system (CNS) white matter such as multiple sclerosis. The importance of mitochondria for white matter is best exemplified in a group of defects of the mitochondria oxidative metabolism called mitochondria leukoencephalopathies or encephalomyopathies. These diseases are clinically and genetically heterogeneous, given the dual control of the respiratory chain by nuclear and mitochondrial DNA, which makes the precise diagnosis and classification challenging. Our understanding of disease pathogenesis is nowadays still limited. Here, we review current knowledge on pathogenesis and genetics, outlining diagnostic clues for the various forms of mitochondria disease. In particular, we underscore the value of magnetic resonance imaging (MRI) for the differential diagnosis of specific types of mitochondrial leukoencephalopathies, such as genetic defects on SDHFA1. The use of novel technologies for gene identification, such as whole-exome sequencing studies, is expected to shed light on novel molecular etiologies, broadening prenatal diagnosis, disease understanding, and therapeutic options. Current treatments are mostly palliative, but very promising novel gene and pharmacologic therapies are emerging, which may also benefit a growing list of secondary mitochondriopathies, such as the peroxisomal disease adrenoleukodystrophy.

Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

“…Currently, impaired mitochondrial respiration and function are proposed as the main causes of several neurodegenerative diseases, including prototypic diseases of the central nervous system white matter such as MS and X-ALD [73,74,75], which are associated with increased levels of 7KC in the plasma and/or cerebrospinal fluid of patients [21,22]. In MS, mitochondria play central roles in axonal neurodegeneration [76].…”

Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

“…Different patterns of MRI abnormalities can support the diagnostic process (Bricout et al 2014;Helman et al 2015). Even though involvement of the basal ganglia is a frequent and wellknown feature of mitochondrial disease, white matter involvement has been increasingly recognized in more recent patient descriptions (Wong 2012;Morato et al 2014).…”

Double Application of Translocator Protein Ligands and RAW Cells Inflammatory Milieu

“…A number of reports show an increase in the number of TSPO binding sites in the central and peripheral nervous systems during inflammation as well as neuroprotective effects by TSPO ligands (Ferzaz et al, 2002;Wilms et al, 2003;Mattner et al, 2011;Girard et al, 2012;Daugherty et al, 2013;Mattner et al, 2013;Bae et al, 2014;Morato et al, 2014). Because the principal effector cells in neuroinflammatory and neuro-degenerative disorders are microglia, monocyte-derived macrophages, macrophages in the perivascular space, the choroid plexus and the meninges (Bogie et al, 2014), the use of the RAW cell line (derived from murine macrophages) was an appropriate choice for this study.…”

“…In a search of ways to decrease inflammation, and in particular-the neuroinflammation, the effects of two TSPO ligands, Ro5-4864 and PK11195, were extensively studied (Zavala et al, 1990;Ferzaz et al, 2002;Casellas et al, 2002;Cunningham, 2013;Bae et al, 2014;Morato et al, 2014). However, their antiinflammatory properties were attributed mainly to changes in the steroid synthesis.…”