report on research results of the mitochondrial encephalomyopathy lactic acidosis and stroke like episodes melas disease project

i ABSTRACT The mitochondrial DNA mutation MTTL1 A3243G causes MELAS syndrome Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes.. MELAS is a maternally inherited diso

VIETNAM GENERAL CONFEDERATION OF LABOR TON DUC THANG UNIVERSITY FACULTY OF APPLIED SCIENCES

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HO CHI MINH CITY, 2023

VIETNAM GENERAL CONFEDERATION OF LABOR TON DUC THANG UNIVERSITY FACULTY OF APPLIED SCIENCES

i ABSTRACT

The mitochondrial DNA mutation MTTL1 A3243G causes MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes) Melas became a

matter of medical record in 1975 MELAS is a maternally inherited disorder, usually associated

with a point mutation in the mitochondrial DNA (mtDNA) at position 3243 in the tRNA gene (1) MELAS is associated with regular strokes the key to differentiating features is the presence of elevated lactate, encephalopathy and mitochondrial myopathy Besides, mitochondrial are particularly valuable in high metabolic tissue the structures that are usually affected by our

sensory systems and internal organ systems because it’s a mitochondrial disorder This activity

points out the disease’s causes, pathological symptoms, and temporary treatment methods of MELAS syndrome

Keywords: Mitochondrial, encephalomyopathy, lactic acidosis, stroke-like episodes ii

INTRODUCTION

Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS)

is amitochondrial disease primarily affecting the nervous system and muscles MELAS comes to us in the form of relapses of stroke-like brain diseases, myopathy and seizures are often

accompanied by sudden focal signs called stroke-like episodes The condition is relentlessly progressive, resulting in neurological impairment by adolescence or early adulthood.

Hi LIST OF CONTENTS

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Figure 1.1 Mitochondrial Figure 1.2 Mitochondrial DNA Figure 2.1 Krebs cycle

membrane The outer membrane covers the surface of the mitochondrion, while the inner

membrane is located within and has many folds called cristae (3) The space between the outer and inner membranes is called the intermembrane space, and the space inside the inner membrane is called the matrix (3) Mitochondria are typically round to oval in shape and range in size from 0.5 to 10 jum In many organisms, the mitochondrial genome is inherited maternally This is because the mother’s egg cell donates the majority of cytoplasm to the embryo The

number of mitochondria per cell varies widely, in humans, erythrocytes (red blood cells) do not

contain any mitochondria, whereas liver cells and muscle cells may contain hundreds or even thousands (4)

1.1.2 Function of Mitochondrial

Mitochondria are called the “Powerhouse of the cell” because mitochondria are organelles within eukaryotic cells that produce adenosine triphosphate (ATP), the main energy molecule used by the cell Mitochondria produce ATP through the process of cellular respiration, aerobic respiration, which requires oxygen(4) The process of producing ATP through the citric acid cycle or Krebs cycle, takes place in mitochondrial This cycle is associated with the oxidation of pyruvate, which comes from glucose, to form the molecule acetyl-CoA (4) Acetyl-CoA is in turn oxidized and ATP is produced The amount of mitochondria in a cell depends on how much

energy that cell needs to produce Muscle cells, for example, have many mitochondria because

they need to produce energy to move the body (4) Mitochondria produce energy from basic components The citric acid cycle reduces nicotinamide adenine dinucleotide (NAD+) to NADH NADH is then used in the process of oxidative phosphorylation, which also takes place in the mitochondrial (3,5) Beyond ATP production, mitochondrial maintain ion homeostasis, produce precursors for macromolecules, such as lipids, proteins, and DNA, and generate and sequester potentially damaging metabolic byproducts such as ammonia and reactive oxygen species In addition, mitochondria are now understood to play active roles in integrating signaling pathways and responses to stressors (5) The latest research on mitochondrial function by NAT (2018) illustrates the wide range of activities of mitochondrial in cell communication through signally

pathways and contacts with other organelles In their Review, Jessica Spinelli and Marcia Haigis discuss the diverse roles of mitochondria in cellular metabolism, including in bioenergetics,

macromolecule biosynthesis, nutrient catabolism, redox homeostasis and waste management

They review how mitochondria provide discrete compartments with functions in oxidative metabolism, biosynthetic pathways and signaling, and highlight the importance of compartmentalization to metabolic functions Pyruvate compartmentalization, glutamine transport and fatty acid oxidation are critical to energy generation (6) Recent research has uncovered a central role for mitochondrial dynamics in cellular stress responses, a topic reviewed by Hajnéezky and colleagues They cover the central role of mitochondria in supporting survival and stress adaptation, and how mitochondria are integral to programmed cell death signaling to remove damaged cells (7) Studies in model systems have also revealed links between mitochondrial quality control in aging and longevity, as well as roles in calctum homeostasis in

skeletal muscle and muscle atrophy Pathways are critical for the maintenance and sense of

mitochondrial DNA and have been implicated in inflammation and immune signaling

ATP synthase Granules

Porins

Intermembrane space

Mitochondrial DNA (mtDNA) is the physical embodiment of the genetic information

encoded in the mitochondrion Technically, the term ‘mitochondrial DNA’ encompasses not only

the mitochondrial genome per se but additional DNA types (e.g., small linear plasmid-like DNAs) that are present in the mitochondria of some organisms(8) Every mitochondrion contains 1 to 15 mtDNA molecules mtDNA copy number per oocyte is highly associated with the probability of developing a healthy ocosperm (9) Mitochondrial DNA (mtDNA) is maternally inherited (10,11) Among these, maternal diseases linked to mitochondrial DNA (mtDNA) mutations are of special interest due to the unclear pattern of mitochondrial inheritance Multiple copies of mtDNA are present in a cell, each encoding 37 genes essential for mitochondrial function (11,12) Even though azygotereceives both maternal and paternal mtDNA at fertilization, the paternal mtDNA is specially targeted for elimination and removed from the

cytoplasm of the zygote during very early embryogenesis (12) The amount of mitochondria

present in a metaphase II oocyte, mature metaphase II cocytes can contain 100,000 mitochondria

and 50,000—1,500,000 copies of the mitochondrial genome (13) Research illustrates the crucial of mitochondrial DNA Without mitochondrial, it will not be possible to synthesize ATP and also if there is a lack of mitochondrial DNA, it will not be possible to carry out the Krebs cycle and

lead to mitochondrial myopathy, encephalopathy and can be diagnosed with MELAS

Genetic mutations cause MELAS syndrome Genetic mutations are changes in a sequence of your DNA, which gives your cells the information they need to work as they should Genetic changes can happen for several reasons, from development to adulthood But if you have MELAS syndrome, you inherited the mutation from your female birthing parent MELAS syndrome is a rare neurodegenerative disease caused by mutations in mitochondrial (mt) DNA affecting mt-tRNA(Leu(UUR)) (13) MELAS syndrome has been associated with at least 6 different point mutations, 4 of which are located in the same gene, the tRNALeu (UUR)gene

The most common mutation, found in 80% of individuals with MELAS syndrome, is an A — G

transition at nucleotide (nt) 3243 in the tRNALeu (UUR)gene An additional 7.5% have a heteroplasmic T — C point mutation at bp 3271 in the terminal nucleotide pair of the anticodon stem of the tRNALeu (UUR)gene Moreover, a MELAS phenotype has been observed associated with an m.13513G — A mutation in the ND5 gene and POLG deficiency (14) Some of the genes (MT-ND1, MT-NDS) affected in MELAS encode proteins that are part of NADH dehydrogenase (also called complex J) in mitochondria, which helps convert oxygen and simple

sugars to energy (15) Mitochondrial diseases are a group of metabolic disorders When the mitochondria are defective, the cells do not have enough energy The unused oxygen and fuel molecules build up in the cells and cause damage The mitochondrial utilize the Krebs cycle to gain the ATP out of glycolysis and so if you have a mitochondrial deficit the pyruvate which is the entry molecule into the Krebs cycle is shunted over into the anaerobic pathway for pyruvate dehydrogenase leading to lactate so the lactic acidosis has increase So whenever we are dealing with a patient who has multiple recurrent stroke-like episodes and has a mitochondrial

encephalomyopathy and lactic acidosis you should think about MELAS 2.2 Symptoms

Mitochondrial are particularly valuable in high metabolic tissue the structures that are

usually affected our brain kidney hearing eye and we have to worry about cardiac conduction deficits but any organ system can be involved because it is a mitochondrial disorder We can test

patients who have mitochondrial encephalopathy, an increase in lactic acidosis and stroke-like episodes or mitochondrial DNA mutation Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, epilepsy, and hormonal imbalances (16)

2.3 Diagnosis

MELAS is diagnosed based on clinical findings and molecular genetic testing Clinical testing may include measurement of lactate and pyruvate concentrations and CSF protein which are elevated m MELAS syndrome Brain imaging techniques such as magnetic resonance imaging (MRI) may be used to look for stroke-like lesions and magnetic resonance spectroscopy (MRS) may be used to look for a lactate peak in the brain (17) An electrocardiogram may be used to diagnose heart rhythm abnormalities and an echocardiogram may be used to diagnose cardiomyopathy Muscle biopsy will usually show ragged red fibers The mtDNA mutations

associated with MELAS can usually be detected in white blood cells, but due to heteroplasmy

(18), other tissue samples may be necessary such as skin, hair follicles, urinary sediment and skeletal muscle Urinary sediment has the best yield for detecting the mutation when compared

to blood, skin, and hair follicles 2.4 Treatment

There is no curative treatment The disease remains progressive and fatal (19,20) Patients and their family members have given consent to the study “Genotype and phenotype in inherited neurological disease(2 1).

i CH3

temporal region to the occipital lobe and also shows a right occipital lesion (d) Magnetic resonance spectroscopy shows an inversion of the J-coupling phenomenon at 1.3 ppm, indicating a lactate peak (22)

CHAPTER 3 CONCLUSION

This report indicates that Melas is a disease related to mitochondrial myopathy caused by

a point mutation inherited from mother to child, leading to a lack of mitochondria that cannot be synthesized into ATP for the body Besides, the report also points out the causes of MELAS, disease symptoms, disease diagnosis and treatment

REFERENCES

1 Kaufmann P, Koga Y, Shanske S, Hirano M, DiMauro S, King MP, Schon EA

Mitochondrial DNA and RNA processing in MELAS Ann Neurol 1996 Aug;40(2):172- 80 doi: 10.1002/ana.4 10400208 PMID: 8773598

https://www.nature.com/scitable/topicpage/mitochondria-14053590/ https://biologydictionary net/mitochondria/#function-of-mitochondria

Rogers, Kara "mitochondrion" Encyclopedia Britannica, 8 Dec 2023, https://www.britannica.com/science/mitochondrion Accessed 17 December 2023

5 Focusing on mitochondrial form and function Nat Cell Biol 20, 735 (2018) https://doi.org/10.1038/s41556-018-0139-7

6 Spinelli, J.B., Haigis, M.C The multifaceted contribution of mitochondria to cellular metabolism Nat Cell Biol 20, 745—754 (2018) https://doi.org/10.1038/s41556-018-0124-

1

7 Eisner, V., Picard, M & Hajnéczky, G Mitochondrial dynamics in adaptive and

maladaptive cellular stress responses Nat Cell Biol20, 755-765 (2018) https://doi.org/10.1038/s41556-018-0133-0

11 Joerg Patrick Burgstaller, Iain G Johnston, Joanna Poulton, Mitochondrial DNA

disease and developmental implications for reproductive strategies, Molecular Human

Reproduction, Volume 21, Issue 1, January 2015, Pages 11-