BIOC- Mitochondrial Functions Flashcards
mt DNA inheritance (6 aspects)
- maternal inheritance (passed directly from mother to child, no sperm contributions)
- 300k mtDNA molecules from egg’s mitochondria
- replicative segregation
- threshold expression
- high mutation rate
- age-related somatic dysfunctions
replicative segregation
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.
heteroplasmy
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
homoplasmy
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.
mitochondrial diseases: nuclear and mt DNA
- most ETC components encoded by nuclear DNA, only 13 subunits by mtDNA
- nuclear DNA shows no maternal inheritance pattern AND is typically autosomal recessive. They are expressed in all tissues (mosaicism may alter this)
- tissues with high ATP demands most affected (pancreatic B cells, skeletal and cardiac muscle, neurons) most affected
Approximately 1 in 5,000 disease-causing mutations in mitochondrial proteins
reduce ATP production capacity in cells.
question about this, seems low
MODY (steps)
Maturity Onset Diabetes of the Young; caused by mitochondrial mutation, disrupted oxphos in B cells results in [ATP] insufficient for the below process
- high blood glucose causes increased ATP production in B cells
- ATP blocks K+ channels, which depolarizes the plasma membrane
- depolarization open Ca2+ channels
- influx of Ca2+ causes exocytosis of insulin containing vesicles
MODY cause
If oxidative phosphorylation in β cells is defective, [ATP] is not sufficient to trigger this process, and insulin is not released.
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?
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?
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?
As the oxphos disease patients age, somatic (spontaneous) mutations
in their mtDNA accumulate and become permanent because
LHON (Leber Hereditary Optic Neuropathy)
AKA sudden vision loss;
begins with painless blurring/clouding and progresses to loss of sharpness and color vision
LHON 2
LHON typically causes bilateral vision loss in early adulthood (ages 15
and 35). It affects the optic nerves and the central nervous system.
LHON mutations
- 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
- A single base change in cytochrome b, component of Complex III
- A mutation in ATP6 affects the proton pore in ATP synthase, leading to low rates
of ATP synthesis while leaving the respiratory chain intact
Leigh’s Disease
rare neurometabolic disorder that affects CNS
Leigh’s diseases affects what ages?
infants between 3 months and 2 years. rarely teenagers and adults
cause of Leigh’s disease
- can be caused by mtDNA mutations
- 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
Leigh Symptoms
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
X-linked Leigh’s disease
A form of Leigh’s disease when the mutated gene is
located on the X chromosome
Leigh’s disease: Tx
thiamine (B1) and oral sodium bicarbonate/ sodium citrate to manage lactic acidosis
MERRF
- Myoclonic epilepsy with ragged-red fiber syndrome (
- MERRF is due to a mutation in the mitochondrial gene responsible for making
a specific tRNA called tRNALys . - Muscular jerking in MERRF arises from problems in producing essential
proteins that rely on mitochondrial tRNAs for their creation. - People with MERRF exhibit abnormal mitochondrial shapes in their skeletal
muscle fibers, which can occasionally contain paracrystalline structures.
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?
LHON
For which of the following mitochondrial myopathies can paracrystalline
protein inclusions be seen in the patient’s muscle electron micrograph?
MERRF
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?
tRNA lys
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?
PDH, CoQ10
Paraganglioma
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.
mutations in what enzymes are assoc. with paraganglioma?
Succinate DH subunits B and D
Pheochromocytoma
- Benign tumor that develops in an adrenal gland
- Pheochromocytoma can be associated with oxidative
phosphorylation defects due to mitochondrial mutations, and genetic
testing can confirm the presence of such mutations - It is a catecholamine-secreting tumor
- Elevated levels of catecholamines and their metabolites including
metanephrines in blood and urine - It can lead to recurrent headaches, palpitations, excessive sweating, and
hypertension
cyt b mutation
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!!!!
In contrast to majority of mtDNA mutations, cytochrome b
mutations are not maternally inherited!!!!
why is this?
lactic Acidosis pathways
ETC interruptions
Anoxia, ischemia, cyanide (inhibits cytochrome c oxidase), CO poisoning
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?
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…
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?
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?
During intense exercise, there may not be enough oxygen available to break down
glucose for energy which can lead to
Hypoxia in any tissue increases …………. production as cells attempt to compensate for a lack of O2
for oxidative phosphorylation and result in …………………….
What happens when protons leak back into the matrix without going through the ATP synthase pore
Which mitochondrial myopathies can show paracrystalline protein inclusions in the patient’s muscle
electron micrograph
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?
In inherited OXPHOS disease involving a subunit of ATP synthase, the most likely mode of inheritance of this
disorder is
