Mitochondrial Diseases: A Case Study

Duchenne Muscular Dystrophy is a sex-linked disease, which is inherited in a recessive fashion (National Human Genome Research Institute, 2013). Over thirty similar genetic disorders exist (Duchenne Foundation Australia, 2015). All types of muscular dystrophy are considered to be a rare disorder (Duchenne Foundation Australia, 2015). Duchenne Muscular Dystrophy is most common in children and causes muscle weakness and wasting, which commonly begins in the lower limbs (Duchenne Foundation Australia, 2015; National Human Genome Research Institute, 2013). The disease itself is caused by changes to the DMD gene, which is responsible for providing instructions regarding the creation of the dystrophin protein in one’s muscles (Duchenne Foundation Australia, 2015). This protein is responsible for protecting muscles from damage, and without it the cells of a person’s muscles deteriorate and symptoms of Duchenne Muscular Dystrophy are exhibited (Duchenne Foundation Australia, 2015). The disease results from changes in the DMD gene, or other genetic changes in a child (Duchenne Foundation Australia, 2015).

Mutations in the POLG gene are related with several mitochondrial diseases, plus Alpers' disease, ataxia-neuropathy disorders, and dominant and recessive types of progressive external ophthalmalgia. An example of the effects of Alpers was an infant was born with a normal birth with no complications. His weight was 8 pounds, the normal weight for a newborn baby. Everything was going well his first 18 months; he was crawling, walking, and even spoke at 12 months. But when he around 19 months old, he experienced anorexia, diarrhea, and vomiting. This was due to lethargy and being hypertonic. He had elevations in liver transaminases and at 30 months developed seizures. He was unable to talk and lost ability to walk at 38 months. After several more

(8). Our preliminary data indicate that alveolar type (ATII) cells isolated from individuals with emphysema have higher nuclear DSBs than control smokers or nonsmokers. Moreover, we observed an increase in mtDNA damage in ATII cells in this disease in comparison with controls. We also found lower XRCC4-like factor (XLF) expression, which is involved in NHEJ pathway (9, 10), in ATII cells in emphysema in comparison with controls. Furthermore, we detected that high oxidative stress induced by exposure to cigarette smoke induces XLF oxidation and localization in mitochondria. DJ-1 is a cytoprotective protein localized in mitochondria. However, we observed that it interacts with XLF in ATII cells in emphysema, which indicates the critical role of XLF/DJ-1 complex in mitochondrial function. In addition, our results suggest that the number of mitochondria is decreased in these cells isolated from emphysema patients in comparison with control smokers and nonsmokers. Our hypothesis is that high levels of ROS in emphysema induce XLF oxidation and mtDNA damage leading to mitophagy and cell death (Fig. 1). Elucidating the molecular mechanisms contributing to mitophagy in primary ATII cells will advance our understanding of the contribution of mitochondria physiology to emphysema development. ATII cells will be isolated from excess tissue obtained from lung transplants of patients with emphysema, Veterans with respiratory problems and from control organ donors

Duchenne Muscular Dystrophy is a sex-linked disease, which is inherited in a recessive fashion (National Human Genome Research Institute, 2013). Over thirty similar genetic disorders exist (Duchenne Foundation Australia, 2015). All types of muscular dystrophy are considered to be a rare disorder (Duchenne Foundation Australia, 2015). Duchenne Muscular Dystrophy is most common in children and causes muscle weakness and wasting, which commonly begins in the lower limbs (Duchenne Foundation Australia, 2015; National Human Genome Research Institute, 2013). The disease itself is caused by changes to the DMD gene, which is responsible for providing instructions regarding the creation of the dystrophin protein in one’s muscles (Duchenne Foundation Australia, 2015). This protein is responsible for protecting muscles from damage, and without it the cells of a person’s muscles deteriorate and symptoms of Duchenne Muscular Dystrophy are exhibited (Duchenne Foundation Australia, 2015). The disease results from changes in the DMD gene, or other genetic changes in a child (Duchenne Foundation Australia, 2015).

The second group of demyelinating diseases,hereditary metabolic disorders, are degenerative diseases and include, among others, the eight identified leukodystrophies (5). Here, 'leuko' means 'white', and refers to the white matter (myelin sheaths) of the central nervous system, and 'dystrophy' means 'imperfect growth or development' (2).. The majority of the leukodystrophies are storage disorders, where the absence or malfunctioning of an enzyme results in the toxic accumulation of chemical substances (5) In each of the so far identified leukodystrophies only one of the

There are several factors being explored as potential causes. Because there are familial cases of ALS, gene-related causes are worthy of investigation with the SOD1 (copper-zinc superoxide dismutase) gene being one of greater interest. Mutations in the SOD1 gene have been found in a fifth of familial cases of ALS (Rosen). Mutations to this gene, rather than having a detrimental effect on its own antioxidant enzyme function, appear to cause disease through toxic gain (Shaw). Oxidative stress and increase in reactive oxygen species can cause cell death, and because mutations in the SOD1 gene can allow this to occur, it could be a potential mechanism for ALS neural degeneration (Wijesk).

To investigate the effects of SS-31 on the mitochondria in cells derived from FRDA patients, we detected MMP with the lipophilic dye JC-1 by measuring a potential-dependent shift in fluorescence from green to red, which reflected its aggregation in mitochondria29. The increased ratio of red versus green fluorescence in patient-derived cells after SS-31 treatment indicated more polarised mitochondria (Fig. 2a). Intracellular ATP level is another pivotal measure of mitochondrial quality. We found that SS-31 treatment significantly raised ATP levels in patient-derived cells (Fig. 2b), indicating increased oxidative phosphorylation. The ratio of NADH/NAD+ in patient-derived lymphoblasts was also measured and was found to be significantly reduced to the levels comparable to the healthy control cells (Fig. 2c). These results indicate much improvement of mitochondrial quality in patient-derived lymphoblasts post SS-31 treatment. Furthermore, we quantified the copy number of mitochondrial DNA and found that SS-31 treatment mildly increased the copy number of mitochondria in patient-derived lymphoblasts (Fig. 2d). Electron microscopic data substantiated these results revealing structural improvements from abnormal cristae in patient-derived cells to regular invagination of the inner membrane after SS-31 treatment (Fig. 2e). Taken together, SS-31 improved the

In this study, the authors discovered a new gene mutation implicated in the onset of Leigh syndrome, a neurodegenerative disease caused by lesions in multiple parts of the central nervous system. The gene mutation was found in a girl with first-cousin parents. Since the girl did not contain mutations of the existing candidate genes for Leigh disease, whole-exome sequence was used to search for a novel homozygous mutation. It was discovered that the patient has a missense mutation in SLC25A46, a gene that codes for a mitochondrial metabolite carrier protein. The authors wanted to determine the role that mutant SLC25A46 has on causing Leigh syndrome. In addition, the authors wanted to make clear the molecular functions of wild-type SLC24A46.

Frataxin is a nucleus encoded mitochondrial protein that is highly conserved in bacteria and in eukaryotic organisms. Reduced frataxin levels in mitochondria have been linked to the neurodegenerative disease Friedreich's ataxia, the most common type of ataxias. At the molecular level frataxin deficiency has been shown to cause higher levels of reactive oxygen species (ROS), among which is the hydroxide radical HO•, a product of the Fenton reaction in which Fe2+ reacts with hydrogen peroxide

In the research done by Deng et al 1993, they concluded that the loss of function was responsible by measuring the enzymatic activity of SOD1 mutants and found it to be on average which is less than half of wild-type SOD1. Since the original findings of linking SOD1 to ALS there now more than a hundred mutations that have been found on SOD1, most these mutations being missense mutations that affect the stability and folding of the enzyme (Beckman et al 2001). The aim of this research paper is to review recent researches and understand the role of oxidative stress that is associated with SOD1 mutations that can possibly lead to

Additionally, carrying out chromosomal microarray was also significant since it also revealed the presence of pathogenic number changes as well as the possibilities of microdeletion that is considered a risk factor with regards to autism, intellectual disability, seizures, as well as malformations. Similarly, measurement of antibodies in three of the samples was also ideal because it provided information of the level – whether high-positive 0r low-positive – of the antibody which is known to block the folate from binding to folate transporter from the blood to the brain. Finally, carrying out a workup for the metabolic disorders following the guidelines suggest by Rossignol & Frye (2011) was also ideal. This is because it enabled determine the elevation levels of biochemical markers that are known for their contribution to mitochondrial dysfunction. These steps were indeed significant because, as is apparent in literature, they give a vivid comprehension on how reduction in mitochondrial roles define mitochondrial deficiencies.

Mitochondrial disease is the malfunctioning of the mitochondria organelle located in every cell of the human body except the red blood cells. These organelles are responsible for the synthesis of 90% of the ATP energy required for a normal bodily function. Consequently if a patient is diagnosed with mtDNA disease, their individual cells will generate less energy than required resulting

Babies that biologically belong to three parents may not be such a distant future after all. In a new study, researchers have shown that a technique called early pronuclear transplantation (ePNT) can produce healthy zygotes out of a sperm cell, the nucleus of one egg cell, and the cytoplasm of another.

Studies in human primary ATII cells: We will assess the function of identified translocated mitochondrial proteins in human ATII cells. We will validate obtained results using these unique cells isolated from control lung donors and patients with emphysema. We found in our preliminary data that ATII cells isolated from individuals with this disease have more mtDNA damage and less mitochondria amount than controls (Fig. 10). We will check expression of identified proteins and genes by western blotting and RT-PCR, respectively in cytoplasmic and mitochondrial fractions. We expect to identify dysregulated proteins which are involved in mtDNA damage repair in primary ATII cells isolated from patients with emphysema.

There is evidence supporting the association between low folate status and mitochondrial DNA instability, and cerebral folate deficiency is relatively frequent in mitochondrial disorders.