Itt írjon a(z) Abnormal_mito-ról/ről

Abnormalities in mitochondrial structure, causes and effects

Contents

Introduction

In this essay we will examine firstly the role and structure of the mitochondrion, and the relevant processes it is responsible for. A key aspect will be the study of the genetic makeup and how the mitochondria is encoded with both nuclear DNA and also mitochondrial DNA, and the importance of maternal inheritance in regards to mtDNA. Knowledge of the genetic background is important if you are to then look at the various disorders and diseases associated with abnormalities in the mitochondria. There is no surprise that the majority of mitochondrial diseases affect tissues and organs which have the highest energy demands such as the heart, brain and muscles since the mitochondria is responsible for the production of ATP Using various scientific papers and articles we will gather information on some of the most common and complicating diseases that arise from disorders in the mitochondria, and what are the causes - Complex deficiencies, Point mutations or mtDNA deletions are areas of major significance, especially when these are inherited by offspring. Diseases and disorders examined include MELAS syndrome, Kearns Sayre syndrome, Alzheimers, and Parkinson’s disease. Secondary disorders and conditions arise from such syndromes and diseases, such as diabetes, exercise intolerance, lactic acidosis and multiple organ failure.

The Mitochondrion

The mitochondrion is a double membraned structure found in most eukaryotic cells. The mitochondria generates most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. hence the name ‘powerhouse of the cell’ (Siekevitz, 1957).

Structure of the Mitochondrion

The organelle is composed of compartments that carry out specialized functions. Because of their double-membraned organization, there are five distinct parts to a mitochondrion. These 5 main compartments or regions are: the outer membrane, the intermembrane space, the inner membrane, and the cristae and matrix. These structures can be seen in figure 1.

Role and processes of mitochondria

The central set of reactions involved in ATP production are collectively known as the citric acid cycle, or the Krebs cycle. Genes in the mitochondrial respiratory chain complex gene group provide instructions for proteins involved in oxidative phosphorylation, also called the respiratory chain. Oxidative phosphorylation is an important cellular process that uses oxygen and simple sugars – Adenosine diphosphate (ADP) to create adenosine triphosphate (ATP), the cell's main energy source. Five protein complexes, made up of several proteins each, are involved in this process(Alston et al., 2017). The complexes are named complex I (NADH dehydrogenase), complex II (Succinate dehydrogenase), complex III (Ubiquinol–cytochrome c oxidoreductase), complex IV (cytochrome C oxidase), and complex V. (ATP synthase)

Genetics of Mitochondrial disease

Mitochondrial diseases

Mitochondrial diseases arise from mutations in either mtDNA or nuclear mitochondrial genes or they can arise from large scale deletions of mtDNA. These abnormalities can cause severe syndromes as well as conditions affecting a multitude of tissues in the body, including the eyes, the heart, muscles, endocrine system and the central nervous system.

Kearns Sayre Syndrome

Kearns Sayre Syndrome (KSS) is a mitochondrial myopathy and a clinical subtype of chronic progressive external ophthalmoplegia (CPEO).The syndrome is defined by the obligatory triad of onset before the age of 20 years, progressive external ophthalmoplegia, and pigmentary retinopathy (van Beynum et al., 2011). In most cases it is caused by single, large scale mitochondrial DNA deletions or mitochondrial DNA depletion (van Beynum et al., 2011). Single, large‐scale mtDNA deletions have a population frequency of 1.5/100 000 with three main associated phenotypes: chronic progressive external ophthalmoplegia, Kearns–Sayre syndrome, and Pearson syndrome (Alston et al., 2017). Chronic progressive ophthalmoplegia (CPEO) is the most common ocular manifestation of mitochondrial myopathies (Al-Enezi et al., 2008). It manifests in the ocular system in many ways eye movement paralysis (ophthalmoplegia), ptosis, oropharyngeal weakness, and proximal myopathy with exercise intolerance (Gustafason et al., 2019). Being a subtype of CPEO, the majority of these effects are also displayed by KSS. It is even believed that the number of tissues affected is higher than so far anticipated. (Finsterer et al, 2020)

Apart from the main three consistent features that characterize KSS (PEO, pigmentary retinopathy and presentation before 20 years of age), this syndrome often displays at least one of the following multisystem implications: cerebellar ataxia, heart block and elevated cerebrospinal fluid protein level.( Yu et al., 2016). Other features include hearing loss, dementia, cardiomyopathy and endocrine disorders, which highlights the impact of this mitochondrial syndrome. Cardiac manifestations in KSS are as high as 50% and sudden cardiac death reported in up to 20% of KSS cases.(Chawla et al.,2008). The most typical cardiac complications of the disease are conduction defects, which usually begin with left anterior fascicular block with or without right bundle branch block (RBBB), progressing sometimes rapidly to complete atrioventricular block. Other cardiac manifestations reported are first or second degree of AV block, QT prolongation, ventricular tachycardia, and cardiomyopathy (Van Beynum et al.,2011)

KSS is usually caused by deletions of mt-DNA, rather than a mutation of the mt-DNA. Due to this it is rarely inherited. single, large-scale mtDNA deletions (SLSMDs) have long been thought to occur sporadically in affected individuals or oocytes. (Gustafson et al, 2019). This suggests that mitochondrial disorders such as KSS develop somatically in the early embryo (Kapunga et al., 2015). Since KSS is caused by deletions of large portions of mitochondrial DNA (mtDNA), this results in the loss of genes involved in the electron chain transport and oxidative phosphorylation pathway, which has effects on energy production. A consistent and conspicuous finding in muscle biopsy samples from patients with KSS is the presence of a population of fibers lacking histochemically detectable COX (cytochrome-c oxidase). Because a proportion of these COX-deficient fibers shows no other morphological abnormality of mitochondria, it has been proposed that they might be precursors of ragged-red fibers and that COX deficiency could be a factor in the pathogenesis of KSS and other disorders(Mita et al. 1989).

This has been further verified, in a publishment by (Finsterer et al,2020) a muscle biopsy from the left lateral vastus muscle in a patient diagnosed with KSS showed cytochrome-C-oxidase (COX)-negative fibers , glycogen depositions, fiber splitting, and ragged-red fibers.In muscle biopsy specimens, the mutant mtDNA accumulate preferentially in ragged red fibers. Ragged red fibers are typically negative for cytochrome oxidase activity (Al-Enezi et al., 2008). The correlation between KSS and absence of cytochrome-c oxidase suggests that the large scale single mtDNA deletion affects the Complex IV enzyme significantly. It most likely involves deletion of at least one of the three mtDNA structural subunit genes - MT-CO1, MT-CO2 or MT-CO3. (Alston et al, 2017) The extent of the deletion of mt-DNA varies in KSS but it is believed it can range from 1.3 to 10 kb, with the most common abnormality being a 4.9 kb deletion from the mitochondrial genome. (Kapunga et al, 2015).