A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging

Scheibye-Knudsen, Morten; Scheibye-Alsing, Karsten; Canugovi, Chandrika; Croteau, Deborah L.; Bohr, Vilhelm A.

doi:10.18632/aging.100546

Cited by 46 publications

(42 citation statements)

References 28 publications

(38 reference statements)

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“…In addition to normal physiological aging, DNA repair-deficient neurodegenerative progeria diseases, including Cockayne Syndrome (CS), Xeroderma Pigmentosum group A (XPA) [99], and Ataxia Telangiectasia (AT) [100], exhibit clinical features similar to classic mitochondrial disorders such as mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) and Myoclonic epilepsy with ragged-red fibers (MERRF) syndromes [101]. XPA and AT demonstrate mitochondrial dysfunction due to reduced SIRT1 activity, stemming from an increase in DNA damage, persistent activation of PARP1, and depletion of NAD + [91, 102].…”

Section: Sirtuins and Mitophagymentioning

confidence: 99%

Mitophagy in neurodegeneration and aging

Fivenson

Lautrup

Sun³

et al. 2017

Neurochemistry International

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Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD+ and urolithins.

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Section: Sirtuins and Mitophagymentioning

confidence: 99%

Mitophagy in neurodegeneration and aging

Fivenson

Lautrup

Sun³

et al. 2017

Neurochemistry International

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241

165

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“…To test this hypothesis, we recently generated an online database of signs and symptoms seen in human mitochondrial disorders, www.mitodb.com (Scheibye-Knudsen et al 2013). We then created a number of online advanced bioinformatics tools to test whether a disorder can be characterized as mitochondrial, based on its clinical signs and symptoms.…”

Section: Mitochondrial Dysfunction and Energy Homeostasismentioning

confidence: 99%

DNA Damage, DNA Repair, Aging, and Neurodegeneration

Maynard

Fang

Scheibye-Knudsen

et al. 2015

Cold Spring Harb Perspect Med

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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.

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“…To understand the mechanism of how transcriptional defects generate mitochondrial changes, we used our recently developed in silico algorithms to predict mitochondrial involvement in the above-listed disorders based on clinical features (11,26). Considering the clinical spectrum of these diseases, hierarchical clustering showed an association between defects in rDNA transcription (SCA17 and HLD7) and mitochondrial disorders, whereas NAIC, TCOF, and DBA did not show this relationship (Fig.…”

Section: Ribosomal Defects Do Not Cause Mitochondrial Dysfunctionmentioning

confidence: 99%

Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

Scheibye-Knudsen

Tseng

Jensen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.Cockayne syndrome | aging | polymerase I transcription | nucleolus | CSA | CSB

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A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging

Cited by 46 publications

References 28 publications

Mitophagy in neurodegeneration and aging

Mitophagy in neurodegeneration and aging

DNA Damage, DNA Repair, Aging, and Neurodegeneration

Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

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