Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38, 518-520

Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Nature Genetics (Impact Factor: 29.35). 06/2006; 38(5):518-20. DOI: 10.1038/ng1778
Source: PubMed


Using a novel single-molecule PCR approach to quantify the total burden of mitochondrial DNA (mtDNA) molecules with deletions, we show that a high proportion of individual pigmented neurons in the aged human substantia nigra contain very high levels of mtDNA deletions. Molecules with deletions are largely clonal within each neuron; that is, they originate from a single deleted mtDNA molecule that has expanded clonally. The fraction of mtDNA deletions is significantly higher in cytochrome c oxidase (COX)-deficient neurons than in COX-positive neurons, suggesting that mtDNA deletions may be directly responsible for impaired cellular respiration.

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Available from: Konstantin Khrapko, Oct 05, 2015
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    • "Furthermore, several relatively common aging-related diseases appear to have a mitochondrial component. For example, mitochondrial dysfunction is a hallmark of b-amyloidinduced neural toxicity in Alzheimer's disease (Lustbader et al. 2004; Tillement et al. 2011); Parkinson's disease patients, as well as elderly individuals, have the burden of mtDNA deletions within substantia nigra neurons (Bender et al. 2006; Kraytsberg et al. 2006); cardiovascular disease is associated with increased production of ROS in mitochondria, accumulation of mtDNA damage, and progressive respiratory chain dysfunction (Madamanchi and Runge 2007; Mercer et al. 2010); and mitochondrial dysfunction characterized by reduced ATP generation appears to have a causal role in features of type 2 diabetes (insulin resistance and hyperglycemia ) (Lowell and Shulman 2005). Declining mitochondrial function over the lifetime of an organism has been shown by several lines of evidence (Corral-Debrinski et al. 1992; Vendelbo and Nair 2011; Chistiakov et al. 2014). "
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    ABSTRACT: Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.
    Cold Spring Harbor Perspectives in Medicine 09/2015; DOI:10.1101/cshperspect.a025130 · 9.47 Impact Factor
    • "Disruption of oxidative phosphorylation (OXPHOS), particularly complex I, is believed to be an important contributor to neuronal loss in PD (Schapira et al., 1990a, 1990b). Dopaminergic neurons in both PD and aged individuals display dysfunctional mitochondria accumulating high levels of mitochondrial DNA (mtDNA) deletions (Bender et al., 2006; Kraytsberg et al., 2006). Mitochondrial disease patients harboring POLG mutations (the polymerase responsible for mtDNA replication) also accumulate mtDNA mutations in dopaminergic neurons leading to nigrostriatal degeneration (Reeve et al., 2013). "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. PARK2 mutations cause early-onset forms of PD. PARK2 encodes an E3 ubiquitin ligase, Parkin, that can selectively translocate to dysfunctional mitochondria to promote their removal by autophagy. However, Parkin knockout (KO) mice do not display signs of neurodegeneration. To assess Parkin function in vivo, we utilized a mouse model that accumulates dysfunctional mitochondria caused by an accelerated generation of mtDNA mutations (Mutator mice). In the absence of Parkin, dopaminergic neurons in Mutator mice degenerated causing an L-DOPA reversible motor deficit. Other neuronal populations were unaffected. Phosphorylated ubiquitin was increased in the brains of Mutator mice, indicating PINK1-Parkin activation. Parkin loss caused mitochondrial dysfunction and affected the pathogenicity but not the levels of mtDNA somatic mutations. A systemic loss of Parkin synergizes with mitochondrial dysfunction causing dopaminergic neuron death modeling PD pathogenic processes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 07/2015; 87(2):371-381. DOI:10.1016/j.neuron.2015.06.034 · 15.05 Impact Factor
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    • "Furthermore, complex I subunits derived from mitochondria from PD patients exhibited oxidative damage consistent with defects in the ETC (Keeney et al. 2006). In addition, mitochondrial DNA deletions were found in the DA neurons from the brains of PD patients (Bender et al. 2006; Kraytsberg et al. 2006). Thus, evidence from these studies strongly implicates mitochondrial dysfunction in the etiology of PD. "
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    ABSTRACT: Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ub-dependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKIN-mediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1-PARKIN pathway will be critical for our understanding of mitochondrial quality control. © 2015 Durcan and Fon; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 05/2015; 29(10):989. DOI:10.1101/gad.262758.115 · 10.80 Impact Factor
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