BIOC- Mitochondrial Functions

Question 1

mt DNA inheritance (6 aspects)

Answer 1

1. maternal inheritance (passed directly from mother to child, no sperm contributions)
2. 300k mtDNA molecules from egg’s mitochondria
3. replicative segregation
4. threshold expression
5. high mutation rate
6. age-related somatic dysfunctions

Question 2

replicative segregation

Answer 2

The mitochondria themselves, in turn, are then distributed randomly between the two daughter cells. This process is known as replicative segregation and can result in significant variability in manifestations of mitochondrial disorders among different tissues and/or patients.

Question 3

heteroplasmy

Answer 3

because of replicative segregation, daughters inherit random variation in terms of mutations that accumulate in the mt DNA.

see the example of cytochrome oxidase in the slide

Question 4

homoplasmy

Answer 4

Homoplasmy is a term used in genetics to describe a eukaryotic cell whose copies of mitochondrial DNA are all identical. In normal and healthy tissues, all cells are homoplasmic.

Question 5

mitochondrial diseases: nuclear and mt DNA

Answer 5

1. most ETC components encoded by nuclear DNA, only 13 subunits by mtDNA
2. nuclear DNA shows no maternal inheritance pattern AND is typically autosomal recessive. They are expressed in all tissues (mosaicism may alter this)
3. tissues with high ATP demands most affected (pancreatic B cells, skeletal and cardiac muscle, neurons) most affected

Question 6

Approximately 1 in 5,000 disease-causing mutations in mitochondrial proteins
reduce ATP production capacity in cells.

Answer 6

question about this, seems low

Question 7

MODY (steps)

Answer 7

Maturity Onset Diabetes of the Young; caused by mitochondrial mutation, disrupted oxphos in B cells results in [ATP] insufficient for the below process

1. high blood glucose causes increased ATP production in B cells
2. ATP blocks K+ channels, which depolarizes the plasma membrane
3. depolarization open Ca2+ channels
4. influx of Ca2+ causes exocytosis of insulin containing vesicles

Question 8

MODY cause

Answer 8

If oxidative phosphorylation in β cells is defective, [ATP] is not sufficient to trigger this process, and insulin is not released.

Question 9

Q1. A patient diagnosed with inherited OXPHOS disease involving a subunit
of ATP synthase. His siblings also exhibit symptoms of the same disease to
a different degree. Which is most likely mode of inheritance of this disorder?

Question 10

A patient diagnosed with inherited OXPHOS disease. His muscle tissue
shows defective cytochrome oxidase. His siblings also exhibit symptoms of
the same disease to a different degree (heteroplasmy). What is most likely
mode of inheritance of this disorder?

Question 11

A child diagnosed with maturity onset diabetes of young (MODY) due to
defective oxidative phosphorylation. What is the result of MODY due to
defective OXPHOS in this child?

Question 12

As the oxphos disease patients age, somatic (spontaneous) mutations
in their mtDNA accumulate and become permanent because

Question 13

LHON (Leber Hereditary Optic Neuropathy)

Answer 13

AKA sudden vision loss;
begins with painless blurring/clouding and progresses to loss of sharpness and color vision

Question 14

LHON 2

Answer 14

LHON typically causes bilateral vision loss in early adulthood (ages 15
and 35). It affects the optic nerves and the central nervous system.

Question 15

LHON mutations

Answer 15

1. A single base change in ND4 Arg → His in complex I, partially defective electron
   transfer from NADH to ubiquinone

2.Replacement of conserved Ala →Val in ND6, sever disease with movement
disorder, impaired speech, and mental disability

3. A single base change in cytochrome b, component of Complex III
4. A mutation in ATP6 affects the proton pore in ATP synthase, leading to low rates
   of ATP synthesis while leaving the respiratory chain intact

Question 16

Leigh’s Disease

Answer 16

rare neurometabolic disorder that affects CNS

Question 17

Leigh’s diseases affects what ages?

Answer 17

infants between 3 months and 2 years. rarely teenagers and adults

Question 18

cause of Leigh’s disease

Answer 18

1. can be caused by mtDNA mutations
2. disruption of complex 1 and 4 are a common cause

PDH mutation and CoQ10

in sum, these mutations result in chronic lack of energy, which impact CNS resulting in progressive degeneration of MOTOR functions

Question 19

Leigh Symptoms

Answer 19

Symptoms progress rapidly

– The earliest signs, poor sucking ability, loss of head
control and motor skills, accompanied by loss of
appetite, vomiting, irritability, continuous crying, and
seizures, involuntary eye movements (nystagmus).

– Overtime, generalized weakness, lack of muscle tone,
and episodes of lactic acidosis, which can lead to
impairment of respiratory and kidney function

Question 20

X-linked Leigh’s disease

Answer 20

A form of Leigh’s disease when the mutated gene is
located on the X chromosome

Question 21

Leigh’s disease: Tx

Answer 21

thiamine (B1) and oral sodium bicarbonate/ sodium citrate to manage lactic acidosis

Question 22

MERRF

Answer 22

1. Myoclonic epilepsy with ragged-red fiber syndrome (
2. MERRF is due to a mutation in the mitochondrial gene responsible for making
   a specific tRNA called tRNALys .
3. Muscular jerking in MERRF arises from problems in producing essential
   proteins that rely on mitochondrial tRNAs for their creation.
4. People with MERRF exhibit abnormal mitochondrial shapes in their skeletal
   muscle fibers, which can occasionally contain paracrystalline structures.

Question 23

A teenager complaining of painless clouding and blurring in his eyes
along with some movement disorder. Family history shows presence of
mitochondrial mutations. This teenager may be suffering from which of the
conditions?

Answer 23

LHON

Question 24

For which of the following mitochondrial myopathies can paracrystalline
protein inclusions be seen in the patient’s muscle electron micrograph?

Answer 24

MERRF

Question 25

Most cases of MERRF are caused by a point mutation in the
mitochondrial gene that encodes a tRNA specific for which of the following
causing this disease?

Answer 25

tRNA lys

Question 26

One of the causes of Leigh’s disease is the disruption of complex I & IV
of electron transport chain resulting in the loss of cellular energy. The other
causes of Leigh syndrome include the deficiency of which of the enzymes?

Answer 26

PDH, CoQ10

Question 27

Paraganglioma

Answer 27

rare neuroendocrine disorder that originates from paraganglia

Paragangliomas can be associated with oxidative phosphorylation
defects, due to genetic mutations, affecting the mitochondria.

For instance, certain genetic mutations related to paragangliomas may
impact the function of enzymes involved in the mitochondrial electron
transport chain.

Mutations in genes such as Succinate Dehydrogenase Complex
subunit B and subunit D have been associated with paragangliomas,
affecting mitochondrial function and contributing to the development of
these tumors.

Question 28

mutations in what enzymes are assoc. with paraganglioma?

Answer 28

Succinate DH subunits B and D

Question 29

Pheochromocytoma

Answer 29

1. Benign tumor that develops in an adrenal gland
2. Pheochromocytoma can be associated with oxidative
   phosphorylation defects due to mitochondrial mutations, and genetic
   testing can confirm the presence of such mutations
3. It is a catecholamine-secreting tumor
4. Elevated levels of catecholamines and their metabolites including
   metanephrines in blood and urine
5. It can lead to recurrent headaches, palpitations, excessive sweating, and
   hypertension

Question 30

cyt b mutation

Answer 30

Cytochrome b mutation resulting in lower cyt bc 1 complex
activity was reported in a 25 year old man in 1993

Replacement of Gly by Asp, Gln, Ser at position 290, 339, 34 alters the structure of cyt b with
lowered catalytic activity of bc 1 complex

In contrast to majority of mtDNA mutations, cytochrome b
mutations are not maternally inherited!!!!

Question 31

In contrast to majority of mtDNA mutations, cytochrome b
mutations are not maternally inherited!!!!

Answer 31

why is this?

Question 32

lactic Acidosis pathways

Answer 32

Question 33

ETC interruptions

Answer 33

Anoxia, ischemia, cyanide (inhibits cytochrome c oxidase), CO poisoning

Question 34

A patient suffering from abdominal discomfort, decreased appetite, diarrhea, along
with, muscle pain, and weakness is diagnosed with lactic acidosis? What cause can
most likely be attributed to her condition?

Question 35

An obese patient is interested in using drugs such as DNP that activate
Uncoupling Proteins (UCPs) to lose weight. A potential side effect of such drugs could
be…

Question 36

Most of the newly synthesized ATP from the mitochondrial matrix is transported
out of the mitochondria for body’s energy-requiring processes as ADP is transported
into the mitochondrial matrix. This transport occurs through which transporter?

Question 37

When a stressor gives the signal for cell death, one early consequence is an
increase in the permeability of the outer mitochondrial membrane, allowing a protein to
escape from the intermembrane space into the cytosol where it binds with ATP and
APaf-1 to form an apoptosome. What is name of that protein?

Question 38

During intense exercise, there may not be enough oxygen available to break down
glucose for energy which can lead to

Question 39

Question 40

Hypoxia in any tissue increases …………. production as cells attempt to compensate for a lack of O2
for oxidative phosphorylation and result in …………………….

Question 41

What happens when protons leak back into the matrix without going through the ATP synthase pore

Question 42

Which mitochondrial myopathies can show paracrystalline protein inclusions in the patient’s muscle
electron micrograph

Question 43

A patient with symptoms of recurrent headaches, palpitations, excessive sweating, and hypertension
and with elevated levels of catecholamines including metanephrines in their blood and urine is most likely
suffering from?

Question 44

In inherited OXPHOS disease involving a subunit of ATP synthase, the most likely mode of inheritance of this
disorder is

Question 45