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1

functions of the mitochondria

-atp production
-regulate cell metabolism (oxidation of sugars/fats, synthesis/breakdown/interconversion of amino acids)
-cell death
-calcium storage
-biosynthesis (heme, steroids, iron sulfur clusters)
-cell signaling via ROS (reactive O2 signaling)
-participate in urea cycle

2

what type of major organs are impacted by mitochondrial disease?

most high energy organs (ex: muscle, eye, brain, heart, liver, GI)

3

mitochondria are composed of...

bigenomic proteins (from both nuclear and mitochondrial gene products)

4

why is mitochondrial-nuclear crosstalk so important?

essential for mitochondrial functions including correct synthesis, import/folding/assembly, and functioning of respiratory chain enzymes

5

Respiratory subunits in mitochondria

complexes I, III, IV, V

all encoded by mitochondrial genome except complex II (succinate dehydrogenase)

6

6 must know facts about mitochondrial DNA (re: inheritance and replication)

1. each mitochondrion has 2-10 copies of mtDNA: tons of cytoplasmic inheritance in each cell

2. mtDNA is maternally inherited

3. mtDNA replication is not dependent on cellular division

4. mtDNA undergoes replicative segregation duirng mitosis and meiosis

5. mtDNA has mutation rate 10-20x higher than nuclear DNA (polymerase is not as good)

6. mtDNA mutation has a threshold expression; when the threshold level is crossed, the cell (thus organ) will suffer

7

there are mutations in mitochondrial genome that cause disease...what are the 4 categories

1. giant deletions (tend to be spontaneous and not inherited)
2. tRNA mutation
3. rRNA mutation
4. mRNA mutation

8

How does nuclear DNA interact with mitochondria? (3 ways)

1. cooperates with mtDNA in synthesis and assembly of multi-subunit enzyme complexes of oxidative phosphorylation

2. encodes all components of protein import machinery

3. encodes transcription factors for mtDNA transcription & replication & for proteins that target mitochondria

9

can mutations in different genes cause the same syndrome?

yes

10

Leigh's syndrome, why is it so interesting?

it is caused by mRNA mutations of complexes I, II, III, and IV. Severity is different depending on the legion.

11

3 possible sources of mutations in mitochondria?

1. nuclear DNA: mendelian inheritance

2. cytoplasmic mtDNA: non-mendelian; maternal inheritance

3. X-linked

12

3 major mtDNA mutations

1. attached to IMM, source of ROS

2. lacks protective histones

3. limited repair system


-copy number mutations also exist

13

missense mutations

aa substitutions

LHON (Lebers hereditary optic neuropathy)

14

biogenesis mutations: tRNA point mutations affects protein synthesis

-MERRF (myoclonus epilepsy and ragged red fibers)
-MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms)

15

insertion-deletion mutations

deletions of 1.3-7.6 kb
-often flanked by direct repeats of nucleotides
-usually no family history

-KSS (Kearns sayre syndrome)
-PEO (Progressive external ophthalmoplegia)

16

mtDNA homo vs. heteroplasmy

homoplasmy - normal

heteroplasmy- diseased/aged

17

explain the mitochondrial genetic bottleneck

primordial germ cell -> primary oocyte -> mature oocyte

primordial has a ton of mitochondria and it splits off into primary oocyte then they mature and you will have different levels of good and mutant mitochondria

low level mutation- offspring unaffected

high level mutation- offspring affected

intermediate level mutation- offspring may or may not be affected

18

Fission and fusion as quality control events

fission- breaks apart the mitochondria and the good parts are distributed, the bad are mitophagy (taken to trash) or if its really bad then apoptosis occurs

the good parts are then fused

after fission there should be a spread out of damaged mtDNA so it can still be below the threshold

19

How are nuclear encoded proteins incorporated?

>90% of mitochondrial proteins have to be imported

Targeting sequence (signal, leader, or presequence)
-20-70 aa
-rich in basic and hydroxylated aa at N-terminus
-can form amphipathic structures
-cleaved by specific peptidases in the mitochondria

Cytosoilic factors (Hsp70): unfolding, need ATP

20

are mitochondria the same in every tissue

no! they are sculpted in a tissue-dependent manner

21

major pathway affecting mitochondrial biogenesis (part that was boxed)

AMPK -> PGC-1a -> expression of multiple mitochondrial genes

22

AMP kinase

phosphorylates PGC-1a and its the main sensor in the cell due to adenylate cyclase (high AMP levels stimulate AMP kinase)

-master metabolic regulator
-maintains nucleotide pools over wide range of enzyme demands
-AMP stimulates glycogenolysis and glycolysis
-AMPK inactive until phosphorylated
-AMP binding inhibits dephosphorylation and allosterically activates
-ATP antagonizes these effects
- >30 downstream targets

23

PGC-1a

induces the expression of multiple mitochondrial genes by driving transcription factors which drive protein synthesis and import into the mitochondria

24

mitophagy

removes damaged good. (cell apoptosis in the substantia nigra for all of these)

25

apoptosis is mediated at the mitochondria

-important during development and in fighting viral infections
-misregulation of apoptosis causes or contributes to a large number of disease
-regulation occurs at 3 steps BUT the committed step is cyt c release
-Bcl-2 proteins control cyt c release
-Bcl-2 proteins come in two flavors:
1. pro-apoptotic (Bax, Bak) or pro-survival (Bcl-2, Bcl-xL, McI1, A1, Bcl-w)
-Pro-apoptotic thought to form channel that allow cyt c (and others) release

26

3 person IVF

potential treatment for mitochondrial disease

mothers nucleus (with unhealthy mitochondria) goes into a donor egg with healthy mitochondria

27

diseases of aging in which mitochondrial dysfunctions are implicated

you are burning fuel and that causes oxidative damage. as you get older this builds up and you start to reach that threshold. this threshold is different for different people and since some people
eat better/exercise more they have different amounts of mitochondrial damage.

1. Normal aging
-reactive oxygen species (superoxide, H2O2, OH- radicals): major mtDNA-damaging agents
-mtDNA deletions accumulate with age
-oxidative phosphorylation normally declines with age

2. parkinson's (paralysis agitans)

3. alzheimer's

28

Mitochondrial dysfunction factor in neurodegenerative diseases

mitochondrial dysfunction and oxidative stress factor in these delayed onset diseases....
-parkinson's
-alzheimer's
-huntington's
-amyotophic lateral scerosis (ALS)

mtDNA mutations arent primary cause of disease
-cause/effect relationship leading to disease currently under investigation but mitochondra do play a central role