Mitochondrial Disorders in the Nervous System

Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Annual Review of Neuroscience (Impact Factor: 19.32). 02/2008; 31(1):91-123. DOI: 10.1146/annurev.neuro.30.051606.094302
Source: PubMed


Mitochondrial diseases (encephalomyopathies) have traditionally been ascribed to defects of the respiratory chain, which has helped researchers explain their genetic and clinical complexity. However, other mitochondrial functions are greatly important for the nervous system, including protein importation, organellar dynamics, and programmed cell death. Defects in genes controlling these functions are attracting increasing attention as causes not only of neurological (and psychiatric) diseases but also of age-related neurodegenerative disorders. After discussing some pathogenic conundrums regarding the neurological manifestations of the respiratory chain defects, we review altered mitochondrial dynamics in the etiology of specific neurological diseases and in the physiopathology of more common neurodegenerative disorders.

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    • "A rendszer sérülésével tehát nagy valószínűséggel elégtelenné válik a IV-es respirációs komplex felépítésében és egy sor, eddig ismeretlen mitokondriális folyamatban szerepet játszó fehérje IMS-be, illetve mátrixba irányuló transzportja [30]. A mitokondriális rendellenességek pedig tipikusan a nagy energia-(ATP-) igényű szöveteket, az idegrendszert és a vázizomzatot érintő tünetekkel manifesztálódnak [33]. "
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    ABSTRACT: ALR is a mystic protein. It has a so called "long" 22 kDa and a "short" 15 kDa forms. It has been described after partial hepatectomy and it has just been considered as a key protein of liver regeneration. At the beginning of the 21st century it has been revealed that the "long" form is localized in the mitochondrial intermembrane space and it is an element of the mitochondrial protein import and disulphide relay system. Several proteins of the substrates of the mitochondrial disulphide relay system are necessary for the proper function of the mitochondria, thus any mutation of the ALR gene leads to mitochondrial diseases. The "short" form of ALR functions as a secreted extracellular growth factor and it promotes the protection, regeneration and proliferation of hepatocytes. The results gained on the recently generated conditional ALR mutant mice suggest that ALR can play an important role in the pathogenesis of alcoholic and non-alcoholic steatosis. Since the serum level of ALR is modified in several liver diseases it can be a promising marker molecule in laboratory diagnostics. Orv. Hetil., 2015, 156(13), 503-509.
    Full-text · Article · Mar 2015 · Orvosi Hetilap
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    • "The term mitochondrial disease is generally ascribed to genetic diseases caused by defects in OXPHOS [5]. Recently, more and more neuromuscular diseases that are not directly linked with OXPHOS deficiency are considered mitochondrial diseases because of involvement of other mitochondrial processes like mitochondrial fusion/fission and mitochondrial protein importation [6]. Even though many mitochondrial diseases are multisystemic, the neuromuscular manifestations are usually the most prominent ones. "
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    ABSTRACT: Mitochondrial structure and function is emerging as a major contributor to neuromuscular disease, highlighting the need for the complete elucidation of the underlying molecular and pathophysiological mechanisms. Following a forward genetics approach with N-ethyl-N-nitrosourea (ENU)-mediated random mutagenesis, we identified a novel mouse model of autosomal recessive neuromuscular disease caused by a splice-site hypomorphic mutation in a novel gene of unknown function, DnaJC11. Recent findings have demonstrated that DNAJC11 protein co-immunoprecipitates with proteins of the mitochondrial contact site (MICOS) complex involved in the formation of mitochondrial cristae and cristae junctions. Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. The causal role of the identified mutation in DnaJC11 was verified in rescue experiments by overexpressing the human ortholog. The full length 63 kDa isoform of human DNAJC11 was shown to localize in the periphery of the mitochondrial outer membrane whereas putative additional isoforms displayed differential submitochondrial localization. Moreover, we showed that DNAJC11 is assembled in a high molecular weight complex, similarly to mitofilin and that downregulation of mitofilin or SAM50 affected the levels of DNAJC11 in HeLa cells. Our findings provide the first mouse mutant for a putative MICOS protein and establish a link between DNAJC11 and neuromuscular diseases.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "In an effort to alleviate mitochondrial disease, recent research offers experimental clinical techniques aimed at preventing the transmission of mutant mtDNA [64, 65]. In patients with mitochondrial disease, the mutant mtDNA is either homoplasmic (all mtDNA copies are mutated) or heteroplasmic (both mutant and wild type mtDNA found in the same individual) [66]. The disease phenotypes are only present in patients with above-disease threshold level of mutant mtDNA. "
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    ABSTRACT: Mitochondria, the energy-generating organelles, play a role in numerous cellular functions including adenosine triphosphate (ATP) production, cellular homeostasis, and apoptosis. Maternal inheritance of mitochondria and mitochondrial DNA (mtDNA) is universally observed in humans and most animals. In general, high levels of mitochondrial heteroplasmy might contribute to a detrimental effect on fitness and disease resistance. Therefore, a disposal of the sperm-derived mitochondria inside fertilized oocytes assures normal preimplantation embryo development. Here we summarize the current research and knowledge concerning the role of autophagic pathway and ubiquitin-proteasome-dependent proteolysis in sperm mitophagy in mammals, including humans. Current data indicate that sperm mitophagy inside the fertilized oocyte could occur along multiple degradation routes converging on autophagic clearance of paternal mitochondria. The influence of assisted reproductive therapies (ART) such as intracytoplasmic sperm injection (ICSI), mitochondrial replacement (MR), and assisted fertilization of oocytes from patients of advanced reproductive age on mitochondrial function, inheritance, and fitness and for the development and health of ART babies will be of particular interest to clinical audiences. Altogether, the study of sperm mitophagy after fertilization has implications in the timing of evolution and developmental and reproductive biology and in human health, fitness, and management of mitochondrial disease.
    Full-text · Article · Jun 2014 · BioMed Research International
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