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1PATH3305 Medical Genetics > Lecture 6: Mitochondrial Genetics in Health > Flashcards

Lecture 6: Mitochondrial Genetics in Health Flashcards

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USMLE® Step 1 flashcards Biology 101 flashcards
1
Q

What happened 3.6 billion years ago…? …6

A
  1. The first signs of life began about 3.6 billion years ago, in the OCEAN
  2. The iron-rich rocks formed before the presence of atmospheric oxygen, and life itself. Found upon these rocks are 3.45 billion-year-old fossil STROMATOLITES, COLONIES OF MICROBIAL CYANOBACTERIA.
  3. The first signs of life began about 3.6 billion years ago, in the ocean.
  4. The water in the ocean protected organisms living there from the dangerous rays of the sun.
  5. These x-rays and gamma-rays are part of the electromagnetic spectrum, which damage living things.
  6. Later, Earth developed an atmosphere.
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2
Q

LIFE ON EARTH …2 BILLION YEARS AGO…6**

A
  1. Primitive Heterotrophic Eukaryote

and

and Autotrophic Alpha Proteobacterium Prokaryote

exits

  1. Eukaryote EATS but DOES NOT DIGEST Prokaryote
  2. Eukaryote keeps BACTERIUM as a SYMBIONT
  3. Symbiont loses many genes and becomes MITOCHONDRION
  4. LIFE EVOLVED TO AS WHAT WE KNOW NOW
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3
Q

Mitochondria are essential for life… EXPLAIN …3

A

1 * Produce >95% of cellular energy
by oOXIDATIVE PHOSPHORYLATION

2 * Mitochondria produce 64 KILOGRAMS of ATP EVERY DAY

3 * SUPPORT MOST of the ACTIVITIES OF OUR CELLS

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4
Q

Mitochondrial how shoes it look like? how much? what does it do?. EXPLAIN …5

A

1 * MITOCHONDRIA can have DIFFERENT SHAPES IN DIVERSE CELL TYPES AND ORGANS

    • TheNUMBER OF MITOCHONDRIA DIFFERS BETWEEN ORGANS AND CELL TYPES …. most of the time depending on energy requirements

3 * MITOCHONDRIA FORM RETICULAR NETWORKS THROUGH RETICULAR NETWORKS THROUGH WHICH THEY COMMUNICATE WITH EACH OTHER.

4 * MITOCHONDRIA ASSOCIATE WITH OTHER ORGANELLES SUCH AS THE ER

5 *MITOCHONDRIA UNDERGO FUSION AND FISSION

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5
Q

Mitochondria are the powerhouse of the cell…

Features of the Mitochondria…3

A

1 * Mitochondria have4 COMPARTMENTS

2 * Mitochondria have their OWN GENETIC MATERIAL known as mtDNA

  1. and their OWN MACHINERY FOR ITS EXPRESSION
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6
Q

ROLE OF MITOCHONDRIA…7

A
  1. Regulate cell death,
  2. ion homeostasis,
  3. fat and carbohydrate metabolism,
  4. hormone and steroid production,
  5. ROS defence and production,
  6. cell signalling
  7. redox regulation.
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7
Q

Energy is produced by oxidative phosphorylation…6

A
  1. During oxidative phosphorylation, electrons derived from NADH and FADH2 combine with O2,
  2. and the energy released from these oxidation/ reduction reactions is used to drive the synthesis of ATP from ADP.
  3. 2H+ 2e+ + 1/2O2 —> H2O + Energy …in cytoplasm
  4. pmf = Dy DpH
  5. Isolated mitos:
    Dy = 180-200 mV
  6. Cells and in vivo:
    Dy = 130-150 mV
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8
Q

The general organisation of a mitochondrion…6 …4 particular structures

A
  1. In the liver, an estimated 67% of the total mitochondrial protein is located in the matrix, 21% is located in the inner membrane, 6% in the outer membrane, and 6% in the intermembrane space.
  2. Each of these 4 regions contains a special set of proteins that mediate distinct functions.
  3. Cristae = are folds in the inner mitochondrial membrane.
  4. Outer membrane:
    - separates the intermembrane space from the cytosol.
    - The whole exchange of metabolites, cations and information between mitochondria and the cell occurs through the outer membrane.
  5. Inner Membrane:
    - is the active site for the electron transport chain and ATP production.
    - Its integrity is crucial for mitochondrial function and depends on the supply of proteins and phospholipids.
  6. Matrix:
    - has several functions. It is where the citric acid cycle takes place.
    - This is an important step in cellular respiration, which produces energy molecules called ATP.
    - It contains the mitochondrial DNA in a structure called a nucleoid.
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9
Q

Mammalian mitochondrial DNA: 12

A

1 * maternally inherited

2 * 2-10 copies per mitochondrion

3 * 1,000-100,000 copies per cell

4 * compact genome, virtually no non-coding
sequences within genes, 16569 kb in size

5 * one of the smallest mitochondrial
genomes

6 * punctuated order of genes

7 * exclusively encodes membrane proteins

    • circular and double stranded

9 * reduced rRNA content but sufficient for
mitoribosome assembly and function

10 * full complement of tRNAs necessary for translation

11 * D-loop contains regulatory elements for transcription
and replication

12 * The D-loop of mtDNA can be used as a unique feature to define phylogenetic relationships between species or define breeding populations

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10
Q

Mammalian mitochondrial DNA…

RNAs, mRNAs, tRNAs numbers

A

2 rRNAs (12S and 16S rRNA)

11 mRNAs

22 tRNAs

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11
Q

Mitochondrial mRNAs: 14

A

1 *“naked” start codons

2 *5’ caps

3 *no introns

4 *Most lack 5’ and 3’ UTRs, Shine-Dalgarno sequences

5 *2 mRNAs are bicistronic
* ATP8/6
* ND4L/4

6 10 mRNAs have poly(A) tails:
….7 Stabilize mRNAs in animals
…8 * Complete their stop codon
…9 * Length of tails is variable

10 *translated by mitochondrial ribosomes

11*Non-universal genetic code:
…12 * AUA is a start (instead of Ile)
…13 * UGA is Trp (not stop)
…14 * AGA and AGG are stop (not Arg)

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12
Q

Mitochondrial mRNAs: Diagram

A

slide 14

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13
Q

Mitochondrial DNA Transcription = 5

A
  1. Mitochondrial DNA
    —- in mitochondrial matrix —-

2.POLRMT and Transcription machinery

  1. TRANSCRIPTION
  2. PROCESSING: ….POLYCISTRONIC TRANSCRIPT
    - RNase P ans RNase Z
  3. MATURATION: RNA transcripts
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14
Q

Mitochondrial DNA …RIBOSOME ASSEMBLY..3

A
  1. RIBOSOME ASSEMBLY
    - 28S …39S- MRPL45
  2. mRNA MODIFICATION
  3. tRNA MODIFICATION
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15
Q

Mitochondrial DNA …TRANSLATION 4

A
  1. TRANSLATION
  2. RESPIRATORY COMPLEXES
  3. PROTEIN IMPORT ..in mitochondrion
  4. Then to NUCLEUS (passed from mitochondrion - cytoplasm - nucleus)
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16
Q

LOOK AT MITOCHONDRIAL DNA …TRANSCRIPTION, TRANSLATION, PROTEIN IMPORT ….

A

SLIDE 18.. UNDERSTAND AND REMEMBER THE PROCESS

17
Q

The mitochondrial genetic blueprint EXPLAIN THE PROCESS…7

A
  1. Protein dna INTERACTIONS
  2. —-> DNase -I cleavage sequencing
  3. CLEAVAGE AND PROCESSING
  4. —> PARE sequencing
  5. rRNA, tRNA, mRNA
  6. GENE EXPRESSION
  7. RNA sequencing
18
Q

Mitochondrial genome

Using next generation technologies we have identified that:…4

A

1 * The mitochondrial genome is ORGANISED AND STRUCTURED

2 * The mitochondrial GENETIC INSTRUCTIONS (RNAs)ARE MORE COMPLEX than previously thought

3 * MITOCHONDRIAL GENE EXPRESSION IS DIRECTLY LINKED TO ENERGY METABOLISM

4 * New RNAs and MODES OF GENE REGULATION

19
Q

The human mitochondrial transcriptome….

Mitochondrial mRNAs: 3

A

1 * There is variation in the abundance of mt-mRNA levels between different tissues and within individual tissues

2 * Make up at least 30% of total RNA in the heart

3 * The stability and half-life of mt-mRNAs is different within cells

20
Q

Mitochondrial ribosome and protein synthesis

Unique structure: 8

A

1
- 2 rRNAs (12S and 16S rRNA)

2
- 28 proteins in the small subunit

3
- 50 proteins in the large subunit

4 * reduced rRNA content

5 * increased protein content

6 * mitochondria specific ribosomal proteins

7 * recognise “naked” start codons

8 * exclusively translate membrane proteins

21
Q

Mitochondrial ribosome and protein synthesis…6

A
  1. E.coli ribosome
  2. Yeast mitochondrial ribosome
  3. mammalian mitochondrial ribosome
  4. initiation
  5. elongation
  6. LOOK AND DIAGRAMS AND UNDERSTAND IN SLIDE 22
22
Q

Unique features of mt-tRNAs: 6

A

1 * full complement required for translation of the 13 polypeptides, no need for additional tRNA import in mammalian mitochondria

2 * 60 sense codons for 22 tRNAs

3 * different classes of tRNAs

4 * Modified nucleotides

5 * Wobble bases

6 * mutations in tRNA genes cause defects in protein. synthesis and lead to disease

23
Q

LOOK AND UNDERSTAND THE TYPES OF mt-tRNAs

A

Type 0

Type I

Type II

Type III

SLIDE 23

24
Q

Mitochondrial tRNA modifications…

Unique features of mt-tRNAs: 3 and the types

A

1
*16 species of modified nucleosides

2
3 mitochondria-specific modifications:
——- 5-formylcytidine (f 5 C)
——-* 5-taurinomethyluridine (τm5 U)
——* 5- taurinomethyl-2-thiouridine (τm5 s2 U)

3
*f 5 C is required to recognize the non-universal AUA codon in addition to the AUG codon

25
Q

Unique features of mt-tRNAs: LOOK AND UNDERSTAND THE Mitochondrial tRNA modifications…

DIAGRAMS

A

SLIDE 24

26
Q

Mitochondrial rRNAs…The mitoribosome is: 5

A

1 * a molecular machine composed of mitochondrial ribosomes and proteins

2 * Mt-rRNA has reduced in size and has been replaced by additional proteins

3 * 2 rRNAs: 12S and 16S that form the small 28S ribosomal subunit and the large 39S ribosomal subunit

4 * TF1BM and NSUN4 methylate the 12S rRNA

5 * A tRNA is also a structural part of the large ribosomal subunit

27
Q

Mitochondrial sRNAs and half-tRNAs

A

UNDERSTAND SLIDE 26

28
Q

Mitochondrial rRNAs

The mitoribosome is:

A

SLIDE 25 DIAGRAM

29
Q

Mitochondrial sRNAs and half-tRNAs

A

SLIDE 27 UNDERSTAND THE DIAGRAMS

30
Q

Mitochondrial long non-coding RNAs…

A

LONG NONCODING RNAs DIAGRAM IN SLIDE 28***IMPORTANT

31
Q

UNDERSTANDING Mitochondrial long non-coding RNAs: 3

A

The mitochondrial long non-coding RNAs:

1 * Highly abundant

2 * Form duplexes

3 * Produced by RNase P

32
Q

Mitochondrial long non-coding RNAs DIAGRAM

A

LOOK AT DIAGRAM IN SLIDE 29

33
Q

Regulation of mitochondrial gene expression:

Mitochondrial gene expression is regulated
by RNA-binding proteins at the level of: 4

A

1 * Transcription

2 * Processing

3 * Maturation

4 * Translation

34
Q

Regulation of mitochondrial gene expression:
DIAGRAM

A

SLIDE 30 …PROCESS DIAGRAM

35
Q

Summary: 4

A

1 * Differential regulation of mitochondrial gene expression can cause mitochondrial dysfunction with varying severities that results in a range of different disorders including, metabolic disease, cardiomyopathies, neurodegeneration, diabetes, cancer and ageing.

2 * Tissues have differential response to mitochondrial dysfunction.

3 * Mutations in either mitochondrial or nuclear genes coding for mitochondrial proteins or
RNAs can cause devastating diseases for which there is no cure nor effective treatments to date.

4 * To understand disease pathology and potential treatments, fundamental discoveries in
mitochondrial biology are necessary.

1PATH3305 Medical Genetics (20 decks)

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