Mitochondrial Function Flashcards
What is the outer membrane of mitochondria permeable to?
small molecules and ions
Describe the permeability of the inner membrane of mitochondria. What structures does it make? What does it contain?
impermeable to most small molecules and ions, including H+
It forms cristae that jut into the matrix
It contains:
- Respiratory electron carriers (I-IV)
- ADP-ATP translocase
- ATP synthase (F0F1)
- Other membrane transporters
What is contained within the matrix of the mitochondria?
- pyruvate dehydrogenase complex
- citric acid cycle enzymes
- fatty acid beta-oxidation enzymes
- amino acid oxidation enzymes
- DNA, ribosomes
- Many other enzymes
- ATP, ADP, Pp, Mg2+, Ca2+, K+
- Many soluble metabolic intermediates
What is the purpose of translocases in the mitochondria? What are they composed of?
Translocases are transport proteins that allow the passage of molecules across the tight mitochondria membrane. Each translocase is compsed of specific membrane spanning helices that bind only specific compounds.
What is the name of the transporters that exchanges ATP for ADP? What type of transporter is this?
ANT (adenine nucleotide translocase)
This is an antiport transporter
What are the types of transporter sresponsible for allowing inorganic phosphate and pyruvate into the mitochondrial matrix?
Symport transporters. They transport a Hydrogen with each phosphate or pyruvate
How is calcium able to enter into the mitochondrial matrix
The mitochondrial matrix is negative, whereas calcium is positive so it is transported by the electrochemical gradient.
What is the name for the nonspecific pores located on the outer mitochondrial membrane? What types of proteins do they bind? Up to what molecular weigt can transport through these pores?
voltage-dependent anion channels (VDACs)
They bind cytosolic proteins, such as hexokinase (HK), which enables HK to have access to newly exported ATP
Up to ~6,000 Da
What type of proteins are VDACs?
At what transmembrane potential are they open? What type of molecules do they prefer?
porin homodimers that form a beta-barrel with a relatively large, nonspecific water-filled pore thorugh the center
They are “open” at low transmembrane potential with a preference fr anions sucha s phosphate, chloride, pyruvate, citrate, and adenine nucleotides
What is the name for the combined transporter junction of an ANT and a VDAC?
What molecules encourage this pore to open? Which molecules encourage it to close?
Mitochondrial permeability transition pore (MPTP)
Open: Ca2+, Pi, ROS,
Closed: cytosolic ATP, low cytosolic pH, electrochemical potential
Which molecules regulate the conformation of ANT?
Which proteins bind VDAC? What do they regulate?
cyclophilin D (CD) and Ca2+
VDAC binds BCl-2 and Bax, which regulate apoptosis, this binding may change the permeability of the outer membrane soa ast to either favor, or block, events leading to apoptosis (such as cytochrome)
Explain why daughter cells show varying degrees of heteroplasmy with relation to mitochondria content?
If some fractin fo maternal mitochondria have a mutant gene, the random distribution of mitochondria durign subsequent cell divisions yields some daughter cells with mostly mutant mitochondria, some with mostly wild-type mitochondria, and some in between.
Different cells in the same tissue are affected to different degrees by the same mitochondrial mutation.
Onset before 20 yrs. of age, characterized by opthalmoplegia, atypical retinitis pigmentosa, mitochondria myopathy, and one of the folowing: cardiac conduction defect, cerebella syndrome, or elevated CSF protein
mtDNA mutation: Deletion contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and mtDNA with a deletion mutation
Kearns-Sayre syndrome
Systemic disorder of oxidative phosphyorylation taht predominantly affects bone marrow
mtDNA mutation: Deletion contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and mtDNA with a deletion mutation
Pearson syndrome
Progressive myoclonic epilepsy, a mitochondrial myopathy with ragged red fibers, and a slowly progressive dementia; onset of sympromts: late childhood to adult
Point mutation: tRNA^lys
myoclonic epilepsy and ragged red fier disease (MERRF)
Progressive neurodegenerative disease characterized by strokelike episodes first occurring between 5 adn 15 years of age and a mitochondrial myopathy
Point mutation: 80-90% mutations in tRNA^leu
Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)
Mean age of onset, 1.5-5 years; clinical manifestatiosn include optic atrophy, ophthalmoplegia, nystagmus, respiratory abnormalities, ataxia, hypotonia, spasticity, and developmental delay or regression
Missense mutations: 7-20% of cases have F0 subunits of the F0Fi-ATPase
Leigh disease (subacute necrotizing encephalopathy)
Late onset, acute optic atrophy
Missense mutation: 90% european and asian cases result from mutation in NADH dehydrogenase
Leber hereditary optic neuropathy (LHON)
Mitochondrial DNA encodes for which subunits of the electron transport chain?
- Complex I
- NADH dehydrogenase (ND1-ND6)
- cytochrome b of Complex III
- the subunits of cytochrome oxidase, Complex IV (COI to COIII)
- two subnits of ATP synthase
How many genes does the mitochondrial chromosome encode for?
How many copies does it have of this genome?
37 genes (13 for respiratory chain, the rest for rRNA and tRNA)
5 copies
Is the nuclear of mitochondrial replication system more effective? What implication does this have for genes?
The mitochondral replication system is less effective than the nuclea, therefore defects int eh mtDNA accumulate over time, which leads to mitochondrial inheritance variation
What is the clinical result of a defect in the nuclear-encoded proteins of Complex IV, COX6B1?
sever defects in brain development and thickened walls of the heart muscle
Which types of cells are the least tolerant to low ATP production? What implication does this have for mitochondrial disease?
neurons, myocytes (skeletal and cardiac) and beta-cells of the pancreas.
They are more affected by mutations in mitochondrial proteins
Explain how diabetes (MODI) can be formed from a mitochondrial mutation.
- In normal situation, when the blood glucose level rises, production fo ATP in beta cells increases
- ATP, by blocking K+ channels, depolarizes the plasma membrane and opens voltage-gated Ca2+ channes. The resluting influx of Ca2+ starts exocytosis of insulin-containing secretory vesicles releasing insulin
- If oxidative phosphorylation in beta cells is defective, [ATP] is never sifficient ot trigger this process and iinsulin is not released
What is the name for the group of mitochondrial encephalomyopathies diseases that affect primarily the brain and skeletal muscle?
Which symptoms does it cause?
List the 4 mutations that can result in this disease
Leber Hereditatary Optic Neuropathy (LHON)
It affects the central nervous system including the optic nerves, cuasing bilateral loss of vision in early adulthood
- Single base change in mitochondrial gene for ND4
- Arg–>His in polypeptide of complex I, defective transeriing an electron from NADH to ubiquinone
- A single base change in mitochondrial gene for cytochrome b
- component Complex III
- Mutation in ATP6 affects the the proton pore in ATOP synthase
- leading to low rates of ATP synthesis while leaving the respiratory chain intact
- Replacement of conserved ALA–> Val in ND6
- sever disease with movement disorder, impaired speech, and mental retardation
Which mytochondria mutation results in uncontrollable muscular jerking?
What is the name of this syndrome?
What is abnormal about the mitochondria in affected cells?
Myoclonic epilepsy with ragged-red fiber syndrom (MERF)
A mutation in the mitochondrial gene tha tencodes a trNA specific for lysine (tRNA^lys)
Skeletal muscle fibers of individuals wtih MERF have abnormally shaped mitochondria that sometimes contain paracrystalline structure
Which mitochondria mutation leads to a condition characterized by benign tumors of the head and neck, commonly in the carotid body?
What is the name of this condition?
Humans with point mutation in complex II subunit near heme b or the quinone-binding site
Paraganglioma
these mutations often result in greater production of ROS
Describe the mutations associated with exercise intolerance.
What is different about inheritance of this disease as compared to other mitochondrial diseases?
Cytochrome b mutation, resulting in lower cty bc1 complex activity
Replacement of a Gly by: Asp, Gln, and Ser, which alters the sturcture of cytochome b and lowers its catalytic acitvity
Cytochome b mutatiosn are not maternally inherited, and are mainly in muscle tissue
What is the name for damage does to the heart as blood flow is being restored to ischemic tissue? How does this happen?
Myocardial reperfusion injury
Damage to mycardium occurs due to rapid restoration of electron transfer with cocomitant generation of ROS
What function does mitochodria serve in adipose tissue?
generate heat to protect vital organs
What function does mitochondria provide in the adrenal glands and gonads?
sites of steriod hormone synthesis
Which protein is associated with head production in brown adipose tissue? How do it work?
Where are the common locations of brown adipose in infants?
UCP1 (thermogenin) is associated with uncoupling proton movement with ATP generation. UCP forms channel through the inner mitochondrial membrane and conducts protons form intermembrane space into the matrix, shortcircuiting ATP synthase.
Infants have brown fat deposits along neck, breastplate, between scapulae adn aroudn the kidneys
Where are the following uncoupling proteins found? What do they do?
UCP1
UCP2
UCP3
UCP4
UCP5
Highly reuglated proteins that, when activated, increase the amount of enegy from fuel oxidation that is being released as heat.
- UCP1 (thermogenin): brown adipose
- UCP2: most cells
- UCP3: skeletal muscle
- may act as transport protein to remove fatty acid anions adn lipid peroxidases from mitochondria, decreasing risk of forming free radicals
- UCP4 and UCP5: nervous system
What percent of our resting metabloic rate is expended to maintain the electrochemical gradient dissipated by basal proton leak?
20%
low level of proton leak across inner mitochondrial membrane– normally partially uncoupled
Which protein acts as a trigger for apoptosis? How does this happen?
cytochrome c, by stimulating caspases
An early consequence of triggering apoptosis is an increase in the permeability of the outer mitochondrial membrane, allowing cytochrom c to escape into the cytosol
What are 4 majory pathways that lead to lactic acidemia?
- Anoxia, ischemia, cyanide, CO poisoning (interruptions to the ET chain)
- Genetic defects in proteins encoded by mtDNA
- Deficiencies in the TCA cycle
- Decreased oxidation of NADh and FAD(2H) in ET chain
All of which encourage glycolysis to proceed anaerobically, therefore producing excess lactate
