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

VIETNAM GENERAL CONFEDERATION OF LABOR TON DUC THANG UNIVERSITY FACULTY OF APPLIED SCIENCES rT REPORT ON RESEARCH RESULTS OF THE MITOCHONDRIAL ENCEPHALOMYOPATHY, LACTIC ACIDOSIS AND ST

VIETNAM GENERAL CONFEDERATION OF LABOR

TON DUC THANG UNIVERSITY FACULTY OF APPLIED SCIENCES

rT

REPORT ON RESEARCH RESULTS OF THE MITOCHONDRIAL ENCEPHALOMYOPATHY, LACTIC ACIDOSIS AND STROKE-LIKE

EPISODES (MELAS) DISEASE PROJECT

MELAS DISEASE

Lecture: Ph.D PHAM MINH TAN Student: HUYNH KIM NGQC- 623H0052

PHÙ CẢM NGỌC - 623H0053

ĐỖ THANH NHU-~ 623H0055

Group : 1

HO CHI MINH CITY, 2023

VIETNAM GENERAL CONFEDERATION OF LABOR

TON DUC THANG UNIVERSITY FACULTY OF APPLIED SCIENCES

rat

REPORT ON RESEARCH RESULTS OF THE MITOCHONDRIAL ENCEPHALOMYOPATHY, LACTIC ACIDOSIS AND STROKE-LIKE

EPISODES (MELAS) DISEASE PROJECT

MELAS DISEASE

Lecture: Ph.D PHAM MINH TAN

Student:

HUYNH KIM NGOC- 623H0052 PHU CAM NGOC - 623H0053

ĐỖ THANH NHƯ - 623h0055

Group: 1

HO CHI MINH CITY, 2023

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 disoder, usually associated

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

sensory systems and internal organ system 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

INTRODUCTION 0A LIST OF CONTENTS

LIST OF FIGURES oii a ‹‹(‹(41 Ÿ5344 aẠ CHAPTER 1 MITOCHONDRIAL AND MITOCHONDRIAL DNA

1.1 Mitochondrial

1.1.1 Structure of Mitochondrial 000i cee eee eteeeeenestestestssnestensnestnesnntesninernesces

1.1.2 Function of MitochondrialL ccccccsccccecsseecesecesecnersvetesectesecnerseervaseenees 1.2 009i 1190 / T44 ii CHAPTER 2 MELAS

2.1 Causes

2.2 Symptoms

2.3 Diagnosis

2.4 Treatment

CHAPTER 3 CONCLUSION 0000 REFERENCES

iv

LIST OF FIGURES

Figure 1.1 Mitochondrial

Figure 1.2 Mitochondrial DNA

Figure 2.1 Krebs cycle

CHAPTER 1 MITOCHONDRIAL AND MITOCHONDRIAL DNA

1.1 Mitochondrial

1.1.1 Structure of Mitochondrial

Mitochondria are thought to have originated from an ancient symbiosis that resulted when a nucleated cell engulfed an aerobic prokaryote(2) Mitochondrial, membrane-bound organelle found in the cytoplasm of almost all eukaryotic cells Mitochondria contain two major membranes(2,3) These membranes are made of phospholipid layers, just like the cell’s outer

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 yum 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

Mitochondrial are called “Powerhouse of the cell” because mitochondrial are organelles within eukaryotic cells that produce adenosine triphosphate (ATP), the main energy molecule used by the cell Mitochondrial produce ATP through process of cellular respiration, aerobic respiration, which requires oxygen(4) The process produce ATP through the citric acid cycle or Krebs cycle, takes place in mitochondrial This cycle associates with the oxidation of pyruvate,

comes from glucose, to form the molecule acetyl-CoA (4) Acetyl-CoA is in tum 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 signalling 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 signalling, 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 Hajnéczky and colleagues They cover the central role of mitochondria in supporting survival and stress adaptation, and how mitochondria are integral to programmed cell death signalling 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 critical for the maintenance and sensing of

mitochondrial DNA have been implicated in inflammation and immune signalling

ATP synthase

Granules

Matrix

Porins

Intermembrane space Mitochondrial DNA

Ribosomes Inner membrane

Outer membrane

Fig 1.1 Mitochondrial

1.2 Mitochondrial DNA

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 has been shown to be highly associated with the probability of developing a healthy oosperm (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 for 37 genes essential for mitochondrial function (11,12) Even though a zygote receives 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 oocytes can

contain 100,000 mitochondria and 50,000—1,500,000 copies of the mitochondrial genome (13) Researches illustrate 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

Mitochondrion

Nucleolus

Outside cell

Fig 1.2 Mitochondrial DNA

CHAPTER 2 MELAS

2.1 Causes

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 a number of 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 in POLG deficiency (14) Some of the

genes (MT-ND1, MT-ND5) affected in MELAS encode proteins that are part of NADH dehydrogenase (also called complex I) in mitochondria, that 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 are utilizing 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 has a mitochondrial

encephalomyopathy and lactic acidosis you should thinking 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 got to worry about cardiac conduction

deficits but really any organ system can be involved because it is a mitochondrial disorder We

can test patients who have mitochondrial encephalopathy, increase in the 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) Electrocardiogram may be used

to diagnose heart rhythm abnormalities and 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

CH,

Pyruvate

Transport protein

Copyright © 2008 Pearion Bosca! prttaning as Pearson Borys

Fig 2.1 Krebs cycle

Figure 2.3 (a) A computed tomography brain scan showing bilateral basal ganglia calcification; the cerebellum shows prominent folia indicating mild cerebellar atrophy (b) Axial T2 brain magnetic resonance image scan showing left temporo-parieto occipital ischemic lesion (c) Axial T2 brain magnetic resonance image scan showing the extension of the parietal temporal region to

the occipital lobe, and also showing a right occipital lesion (d) Magnetic resonance spectroscopy showing inversion of J-coupling phenomenon at 1.3 ppm, indicating 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

https://doi.org/10.1038/s41556-018-0133-0

8 https://doi.org/10.1016/B978-0-12-374984-0.00958-X

9 May-Panloup P, Chretien MF, Malthiery Y, et al Mitochondrial DNA in the oocyte and the developing embryo Curr Top Dev Biol 2007;77:51-83

10.Genet_ Mol Biol 2020; 43(1 Suppl 1): ¢20190095 Published online 2020 Mar

2 doi: 10.1590/1678-4685-GMB-2019-0095

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

disease and developmental implications for reproductive strategies, Molecular Human

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

22, https://do1.org/10.1093/molehr/gau090

12 https://www.researchgate net/publication/

13 https://read.qxmd.com/read/25 149473/the-ros-sensitive-microrna-9-9-controls-

the-expression-of-mitochondrial-trna-modifying-enzymes-and-is-involved-in-the- molecular-mechanism-of-melas-syndrome?redirected=slug