Mitochondrial Disease | Nursing Homework Help

Mitochondrion is the cell power house, they are responsible for energy production in energy-intensive tissues like brain, regulate Ca+2 signaling and control cell death. Mitochondrial use oxygen extensively and lack protective histone proteins, hence vulnerable to oxidative stress (ROS)-causing damage to its genome (mtDNA) (Onyango et al., 2017). All body process relies on it for energy. Fault or digression from its normal function results into unwanted results. Mitochondrion consumes oxygen to synthesize ATP (adenosine triphosphate).  This is synthesized by more than 100 proteins. This is referred as respiratory chain complexes, found in the inner mitochondrial membrane. Mitochondrial dysfunction is implicated in neurodegeneration and ageing. Both α and β haemoglobin (Hba and Hbb) are found to be altered in their distribution from degenerating brain (Chinnery et al., 2012). A number of diseases are as a resultant to mitochondrial dysfunction. Majority of them have been associated with a change in structure. The change in structure is attributed to a number of proteins. Evidence of gene and proteins interaction has well been documented.  Advanced age is a primary risk factor for neurodegeneration, where Hb proteins come into the mix. Mitochondrial diseases are inherited neurological disorders, as a result of mutations in mitochondrial or nuclear DNA. Diseases that are as a result of this are Parkinson disease and Alzheimer.

Alzheimer Disease (AD)

Alzheimer’s disease (AD) is single largest cause of dementia. Oxidative stress is a key feature in pathophysiology of AD, mitochondrial role in AD pathogenesis has been studied intensely. It is an autosomal dominant form of inherited mutation, in precursor protein gene. Mitochondria contain several copies of mtDNA. This is important in downplaying any mutation that may occur (Yan, Wang & Zhu, 2013).  However, mitochondrial toxins can elicit a similar pathology to the disease (Perfeito et al., 2012).  Reactive oxygen species (ROS) usually cause oxidative stress that lead into mutations.  These mutations may gain momentous deleterious effects that result in change of function in the mitochondria. The mutation usually occurs either in the mtDNA or nuclear genes, this end up being rooted in the nuclear genome producing several variant. These mutations occurs at the site of mtDNA transcription and replication regulatory elements; therefore, interfering with the production of the proteins Hba and Hbb. Haemoglobin is one of the protein coded for by Hba and Hbb, the major role of haemoglobin is oxygen transport to the cortex of the brain cells. Once the haemoglobin is altered it result to loss of function and neurodegeneration occurs. MtDNA occurs in haplogroups, this influence the risk of AD whose parents suffer from dementia. However, only maternal line can pass on the genes. Some of the mutations are pathogenic, also referred to as heteroplasmy.

Role of Mutation in Pathophysiology of Alzheimer (AD)

Mutation has been the leading cause of Alzheimer disease; it is associated with over 200 different molecules showing defects with patients diagnosed with mitochondrial disease. Point mutation is the major ones affecting various structural subunits of the respiratory chain. These in turn compromise the integrity of protein synthesis via RNA genes (A Celardo et al., 2014).  Recessive form of disease is as a result of loss of function due to mutations, in genes encoding proteins. This intrinsically localize in mitochondria (phosphatase and tensin homologue-induced putative kinase 1, DJ-1). Deletions remove one or more of the essential genes. While duplications is associated with mtDNA deletions.  Mammalian cells are known to contain several copies of mtDNA tightly regulated through tissue specific manner. While sporadic changes occur over time. Tissues or organs that contain many affected cells manifest clinical features of the disease. Mutations differ from person to person and adjacent cells. Some of the mutation that occurs is missense mutation in homozygous state. Usually caused by single homozygous change, the genes involved are 5, 11, and 82 in T8993G in the mitochondrial genome. The effects caused are deleterious and the mutations are pathogenic.

Role of Regulatory Genes and Structural Genes in Alzheimer Disease

Nuclear genome is usually coiled around histones to form nucleosomes. The histone proteins are specifically modified to regulate gene expression. Since histones allows transcription of DNA to RNA, followed by post transcription to mRNA to polypeptide and eventually proteins. Nuclear encoded mitochondrial proteins are translocated into mtDNA. Genes that are responsible for intra- mitochondrial protein synthesis are encoded here. However, the genome is not histone bound. Messenger RNA and miRNA are transcribed from the nuclear DNA, this can interfere with mRNA inducing degradation and suppressing translation. Mitochondrial biogenesis regulation is via peroxisome proliferator-activated receptor g coactivator-1 a (PGC-1a). Switching on different transcription factors in return, notably nuclear respiratory factors 1 and 2 proteins (NRF-1 and NRF-2), others involved  include estrogen-related receptor alpha (ERR-a), mitochondrial transcription factor A (TFAM) ( NRF-1 and NRF-2 regulate transcription of nuclear and mitochondrial genes, involved in OXPHOS, electron transport (complex I–V), mtDNA transcription/replication, heme biosynthesis, protein import/assembly, ion channels, shuttles, and translation (Onyango et al., 2017). This indicates a switch on mechanism that triggers a change of the structural gene, and translation or suppression of regulator gene. Hence process shows a well-balanced mechanism that knows when to switch on gene expression and when to suppress it. However, in emergence of the disease both structural and functional genes have a hand in the disease process. When structural genes are not transcribed, then the role of the mitochondria is affected.  Regulatory genes on the other hand, are overwhelmed by sporadic alterations that either occurs as a result of mutations.

Role of Proteins in Mitochondrial Disease

Normal proteins in mitochondria are hemoglobin denoted as (Hba and Hbb).  The main role of hemoglobin is oxygen transport; hemoglobin bides oxygen and transports it to the brain cells. Since the brain is an energy extensive organ with no mechanism to synthesis its own energy. A number of proteins are involved in control of mitochondrial disease. This process is called mitophagy; where dysfunctional mitochondria are engulfed selectively by autophagosomes, degraded by lysosomes and recycled in the cell (Rugarli and Langer, 2012; Yan et al., 2012). Any deviations in the mitophagic pathway have been deleterious resulting to AD.  Excess reactive oxygen species (ROS) function as an Autophagy trigger. They interfere with normal protein translation hence a correction mechanism has to be put in place. PTEN-induced putative kinase 1 (PINK1) modulate mitophagy. Ubiquitin ligases, target faulty mitochondria for destruction.  Erythroid 2-related factor 2 (Nrf2) which is a transcription factor regulates expression of nuclear genes (Peterson et al., 2012).  Protein kinase C-delta (PKCδ) is induced by increase in ROS; other molecules are signaled such as Abl tyrosine kinase- this lead to non-apoptotic cell death. AMPK controls mitochondrial metabolism and targets Acetyl CoA carboxylase-2 (ACC2). Playing a major role in mitochondrial homeostasis this ensures that only functionally viable mitochondria are retained. Biogenesis is through activation of PGC-1α and mitophagy through ULK1 activation and mTOR inhibition this ensures homeostasis is achieved. This ensures that the cells are very well regulated at the cellular level.

Management

A molecular diagnosis for mitochondrial disease is usually a complex process, both clinically and genetically.  A lot of advances have been made especially in the genetic approach. Complementing the traditional- histological and biochemical approach. Whole-genome sequencing (WGS) has the benefit of diagnosing  mitochondrial disease in patients not suspected of the disorder, as well as diagnosing non mitochondrial disorder that mimic mitochondrial disease. Phenotyping and sequencing give additional benefits of a better diagnostic option (Schon et al., 2020).  Mitochondrial disorders have been shown as a common cause of inherited disease. Traditionally associated with difficulties in diagnosis and treatment, new sequencing approaches, especially whole-genome sequencing (WGS), have dramatically introduced a breath of fresh air. Analysis of both nuclear and mitochondrial DNA (mtDNA) allows shorter turnaround time diagnosis for the vast majority of patients

 

Parkinson’s disease (PD)

This is a debilitating movement disorder caused by perturbations in mitochondrial structure, distribution and function. Pathogenesis of these diseases remains unknown. Evidence points at oxidative stress as the main cause of PD, linking oxidative stress to the onset of neuronal death and neural dysfunction.  Mitochondrial dysfunction is prominent feature in these diseases. Changes in mitochondrial DNA or mitochondrial dynamics, results in neurodegeneration.  Since mitochondria are morphologically different any change in structure and distribution has an overall effect in hemoglobin. Hemoglobin is located within the neurons and not to any particular organelles.  Proteins (Hbb and Hba) are very much involved. However, a significant difference is noted when brain tissue are compared with muscle cells. The later displaying high levels of mitochondria; this explains well why this disease is associated with ageing and neurodegeneration.

Conclusion

Mitochondrial diseases revolve around alteration of function and structure.  Hemoglobin plays a central role; epigenetics are at the center of it, since hemoglobin is a member of the globular proteins. Globular proteins are characterized by eight alpha helical sections together they make up the globular fold. They are tasked with diverse functions, oxygen bidding- regulation and gene expression as well as terminal oxidase activity. Hypoxia leads to dementia, neurodegeration affect amyloid β (AB) expression, AB interacts with Hb. Anaemia is a common finding in the aged connected to circulating Hb levels and mitochondrial Hb. Mutation play a major role in all this. This has shaped human evolution in response to environment. Polymorphism occurs while men have been noted not to pass these defects to their off springs, only maternal relatives carry this faulty mtDNA. Polymorphism affects the CG dinucleotide. Splicing errors have occurred and exons have not been spared either. DNA methyltransferase 1 (DNMT1) target pre-peptide sequence upstream of mature peptide.  Regulation of mtDNA is through methylation this control expression. Mitochondrial disease is a well-orchestrated protein-protein interaction, gene regulation and expression. Influence of environmental factors on mutation, suppression of mtDNA methylation compensate mtDNA damage. Mitochondrion diseases can be controlled by minimizing ROS through use of antioxidants including vitamin E.

 

References

A Celardo, I., Martins, L. M., & Gandhi, S. (2014). Unraveling mitochondrial pathways to P arkinson’s disease. British journal of pharmacology, 171(8), 1943-1957.lzheimer’s and Parkinson’s diseases. Front Biosci (Landmark Ed), 22, 854-872.

Chinnery, P. F., Elliott, H. R., Hudson, G., Samuels, D. C., & Relton, C. L. (2012). Epigenetics, epidemiology and mitochondrial DNA diseases. International journal of epidemiology, 41(1), 177-187.

Onyango, I. G., Khan, S. M., & Bennett Jr, J. P. (2017). Mitochondria in the pathophysiology of Alzheimer’s and Parkinson’s diseases. Front Biosci (Landmark Ed), 22, 854-872.

Rugarli, E. I., & Langer, T. (2012). Mitochondrial quality control: a matter of life and death for neurons. The EMBO journal, 31(6), 1336-1349.

Schon, K. R., Ratnaike, T., van den Ameele, J., Horvath, R., & Chinnery, P. F. (2020). Mitochondrial diseases: a diagnostic revolution. Trends in Genetics.

Yan, M. H., Wang, X., & Zhu, X. (2013). Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radical Biology and Medicine, 62, 90-101.

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