Mitochondrial Disorders in the Nervous System

Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Annual Review of Neuroscience (Impact Factor: 22.66). 02/2008; 31(1):91-123. DOI: 10.1146/annurev.neuro.30.051606.094302
Source: PubMed

ABSTRACT 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.
    Orvosi Hetilap 03/2015; 156(13):503-509. DOI:10.1556/OH.2015.30119
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    • "Although HD is a Mendelian dominant disorder, and the mutation is fully penetrant and predictive, other above-mentioned genetic markers vary widely in the degrees to which they contribute to disease in various patients. Psychiatrists could also order other GTs for medical conditions that can cause psychiatric symptoms, such as mitochondrial disorders, porphyria, and other monogenic disorders (Dimauro and Schon, 2008; Simon and Herkes, 2011). Genetic markers associated with psychiatric pharmacogenomics are also being sought, identified, and used. "
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    ABSTRACT: We examined how 372 psychiatrists view genetic aspects of mental disorders and behaviors and use genetic tests (GTs). Most thought that the genetic contribution was moderate/high for bipolar disorder, schizophrenia, depression, Alzheimer's, intelligence, creativity, anxiety, and suicidality. In the past 6 months, 14.1% ordered GTs, 18.3% discussed prenatal testing with patients, 36.0% initiated discussions about other GTs, 41.6% had patients ask about GTs, and 5.3% excluded GT results from patient records. Many thought that GTs; were available for schizophrenia (24.3%) and major depression (19.6%). Women were more likely to report that patients asked about GTs; and were less certain about the degree of genetic contribution to several disorders. Psychiatrists perceive strong genetic bases for numerous disorders and traits, and many have discussed and ordered tests for GTs, but have relatively limited knowledge about available tests. These data suggest possible sex differences in psychiatrists' beliefs about genetic contributions to disorders and have implications for future research, education, policy, and care.
    Journal of Nervous & Mental Disease 06/2014; DOI:10.1097/NMD.0000000000000154 · 1.81 Impact Factor
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    • "It has been suggested that when the mitochondrial potential is lost, PINK1 is stabilized (Jin et al., 2010; Narendra et al., 2010) and is able to phosphorylate Parkin at serine 65 (Shiba-Fukushima et al., 2012) and to recruit Parkin onto the mitochondria, where it ubiquitinates a number of mitochondrial membrane proteins, leading to the recruitment of p62 (Geisler et al., 2010) and ULK1 (Mizushima , 2010) to carry out mitophagy. Defects in mitophagy can lead to the accumulation of dysfunctional mitochondria, which is a characteristic of aging-related diseases (Chan, 2006; DiMauro and Schon, 2008; Palikaras and Tavernarakis, 2012) (such as heart failure, Alzheimer disease, and Parkinson disease) and cancers (Kim et al., 2011). Thus, deciphering the regulatory mechanism of mitophagy holds promise for fighting these currently incurable diseases. "
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    ABSTRACT: Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality control via selectively removing damaged or unwanted mitochondria. Interactions between LC3 and mitophagy receptors such as FUNDC1, which harbors an LC3-interacting region (LIR), are essential for this selective process. However, how mitochondrial stresses are sensed to activate receptor-mediated mitophagy remains poorly defined. Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation. Our results reveal a mechanistic signaling pathway linking mitochondria-damaging signals to the dephosphorylation of FUNDC1 by PGAM5, which ultimately induces mitophagy.
    Molecular cell 04/2014; 54(3). DOI:10.1016/j.molcel.2014.02.034 · 14.46 Impact Factor
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