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

Abstract

The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a clustering algorithm, a disease network, a mitochondrial barcode and two scoring algorithms. Using these tools we detected mitochondrial involvement in a number of diseases not previously recorded as mitochondrial. As a proof of principle Cockayne syndrome, ataxia with oculomotor apraxia 1 (AOA1), spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-telangiectasia have recently been shown to have mitochondrial dysfunction and those diseases showed strong association with mitochondrial disorders. We next evaluated mitochondrial involvement in aging and detected two distinct categories of accelerated aging disorders, one of them being associated with mitochondrial dysfunction. Normal aging seemed to associate stronger with the mitochondrial diseases than the non-mitochondrial partially supporting a mitochondrial theory of aging.

Mitophagy in neurodegeneration and aging

“…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].…”

DNA Damage, DNA Repair, Aging, and Neurodegeneration

“…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.…”

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

“…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.…”