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Seminario 15 Patrones de herencia no clásicos 1 - Tomas Falzone — Transcript

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0:03Hello, how are you? Today we are going
0:07to start seminar number 16. I recommend
0:10watching numbers 16 and 17. Next, we
0:13are going to talk about non-classical
0:16inheritance patterns. This is going to
0:20be seminar number 1 on non-classical
0:22inheritance patterns, where we are
0:24going to focus on mitochondrial
0:26inheritance. Then we are going to watch
0:30seminar number 17, which is classical
0:32patterns 2, where we are going to talk
0:35about triplet expansion and also
0:37imprinting. So, to start today's
0:44seminar, we are going to talk about
0:51these three possibilities that involve
0:53inheritance patterns that do not follow
0:55classical patterns. And we are going to
0:59understand why. We are going to
1:01understand that some of these patterns
1:04could have classical behavior once they
1:06are determined within a family. Okay?
1:11Primarily in diseases with teplete
1:13expansion, and in the following seminar
1:15we will also see the imprinting
1:17phenomenon, but today or now we are
1:19going to focus on mitochondrial
1:21inheritance and, to do so, we are going
1:24to try to understand the molecular and
1:29inheritance mechanisms associated with
1:31these mitochondrial entities. The
1:36concept of threshold that is present in
1:40these diseases is associated with a
1:43cellular energy balance that determines
1:46when, under certain conditions, a
1:49disease phenotype appears given a
1:51coexistence of healthy and damaged
1:54mitochondria. To understand the
2:00diagnostic approaches in order to
2:03determine or understand the anomalies
2:06or molecular mechanisms in
2:08mitochondrial diseases and relate the
2:11characteristics of the trees in order
2:14to determine or discriminate it from
2:17other entities. To begin this workshop,
2:24we are going to go back to the 80s with
2:27the advances in sequencing and with the
2:31first determination of the organization
2:34and sequence of the mitochondrial
2:37genome. We know that inside a
2:41eukaryotic cell we have the nucleus
2:43surrounded by a double membrane with
2:46nuclear pores, where the genetic
2:48information of this eukaryotic cell is
2:50found. This cell is diploid and has two
2:53sets of chromosomes organized
2:55differently within this nucleus. We
2:59know that these eukaryotic cells also
3:01have mitochondria, and these
3:02mitochondria are the energy-providing
3:04machinery. However, we know that
3:06mitochondria have their own DNA, which
3:08is very different from mitochondrial
3:10DNA and that allows these mitochondria
3:13to generate new mitochondria from the
3:17duplication of their mitochondrial DNA.
3:19And this DNA was understood in detail
3:22only in the 80s and began to allow us
3:25to establish major differences between
3:28the information stored within
3:31mitochondrial DNA and the information
3:34stored in nuclear DNA. If we observe
3:40the structure of mitochondrial DNA, we
3:43see that it is a circular
3:45double-stranded structure, very similar
3:47to a plasmid, very similar to bacterial
3:50DNA, which has the ability to replicate
3:53within its structure. There are several
3:59copies of these DNA strands within the
4:03same mitochondrion, and when it was
4:07evaluated at the level of coding of
4:10this mitochondrial DNA, it was observed
4:15that it encodes only 13 genes that
4:18encode proteins, it encodes 22 genes
4:24that are going to be involved in the
4:26production of proteins, mitochondrial
4:29transfer RNAs, and rifosomal RNA genes.
4:34So, it has 37 genes, most of which are
4:37RNAs, and 13 proteins that are encoded
4:40in the mitochondrial genome, which are
4:43going to be resident and structural
4:46proteins of the mitochondrial function
4:49that we are going to see today. In
4:57addition, we can understand that the
5:00mitochondrion has a double membrane
5:02structure, which is unusual because it
5:05has a structure that has an outer
5:07membrane that has different membrane
5:10properties than the structure of the
5:13inner membrane. And what we can observe
5:17in the inner membrane is that it forms
5:19or produces these invaginations, okay?,
5:22formed mainly by these membranes that
5:25protect the mitochondrial matrix and we
5:27are going to call them the
5:29mitochondrial cristae. So, this
5:32structure is a very defined structure,
5:34a very elaborate double membrane
5:36structure that gives significant
5:40characteristics to the mitochondria
5:43associated with the production of
5:45anarchy. Well, the inner membrane is
5:48the matrix. This is what I just said.
5:51So, if we observe mitochondrial DNA, if
5:54we observe the structure of the
5:56mitochondria with double membrane, if
5:59we observe the possibility of changing
6:02the number of mitochondria in a cell by
6:05fission and fission mechanisms, we
6:07begin to understand that there is,
6:10around, the identification of how the
6:12mitochondria was, an organelle
6:15incorporated into the karyotic cell,
6:19eukaryotic cell with a theory called
6:21the endosymbiosis theory. In an
6:24ancestral cell that already had a
6:27defined nuclear structure, an
6:31internalization, an invagination, an
6:35incorporation of a bacterium occurs, in
6:39this case an aerobic bacterium, capable
6:46of producing energy by consuming oxygen
6:51and allowing this ancestral eukaryotic
6:59cell to incorporate higher energy
7:01levels. Once this aerobic bacterium
7:05enters this eukaryotic cell, it is
7:08incorporated; both benefit and remain
7:11in a system now of a eukaryotic cell
7:14with mitochondrial organelles that
7:17begins to proliferate, and it is one of
7:21the indications or indicators that
7:23these high energy levels could begin to
7:26cause these cells to begin to associate
7:29into more multicellular organisms and
7:32not unicellular ones. Later, in this
7:36theory of endosymbiosis, a second
7:38endosymbiosis is proposed in a type of
7:40eukaryotic cell that already had
7:42mitochondria, which are produced by the
7:44incorporation, in this case, of a
7:46photosynthetic bacterium capable of now
7:48producing modern photosynthetic
7:50organisms. Okay? And this is the
7:54heterotrophic eukaryote. This idea has
7:59several supports, supported by the
8:02observation of different
8:04characteristics of the mitochondria.
8:07One of the ones I mentioned is the
8:09double membrane. So, if this bacterium
8:11was incorporated into the cell, it was
8:14invaginated in an external membrane,
8:16sorry, a plasma membrane that allowed
8:18it to have a double membrane structure
8:21and preserve or favor the formation of
8:23mitochondrial cristae in the structure,
8:26which are going to be important for the
8:28production of energy. We are talking
8:35about the two membranes of the
8:36mitochondria. The external membrane has
8:39pores or structures capable of allowing
8:41certain proteins that are presented
8:43through these pores to pass through in
8:45a regulated manner. It also possesses
8:49an internal membrane with a lower
8:51degree of permeability; this is
8:53significant in this specific case, and
8:55it is attributed to the presence of
8:57cardiolipin. It is important because it
9:00will allow different gradients to occur
9:07between the intermembrane space and the
9:10mitochondrial matrix, which we will see
9:12later. It has ion transporters and
9:15proteins involved in oxidative
9:17phosphorylation and the respiratory
9:19chain in its internal membrane.
9:22Furthermore, we know that the matrix
9:25contains different enzymes, many
9:28enzymes involved in pyrubate
9:30hydrogenase, in the production of
9:33species that are going to be electron
9:36transporters through the Cress cycle
9:39and the beta oxidation of fatty acids.
9:44So, the mitochondria is an organelle
9:47established for a large production of
9:49different molecules or modification of
9:51different molecules that are ultimately
9:54responsible for the production of high
9:56levels of energy. We had talked about
10:01the DNA level, which has a genetic code
10:04that can be a circular DNA structure
10:07similar to a prokaryote. Furthermore,
10:11the genetic code is not similar to that
10:15of nuclear DNA, where some
10:17trinucleotides code differently, more
10:20similar to what would be prokaryotic
10:23DNA than to nuclear eukaryotic DNA. It
10:29is a circular and naked DNA, okay? and
10:32it has repair mechanisms that are not
10:35as developed as nuclear repair
10:37mechanisms. That is why it is more
10:40prone to modifications or mutations.
10:52Wait, what do I have to do? So, we can
11:05see that the structures of the
11:07ribosomes also have a difference when
11:09we compare them with the ribosomes of
11:11the coding structure in the nuclear
11:14genome. So, we have many indications
11:16that the mitochondria is of prokaryotic
11:22origin and has been introduced into the
11:25eukaryotic genome to gain higher energy
11:27levels. That also determines that there
11:31are inhibitors that we know today to
11:35establish a prevention system when we
11:41have bacterial infections. Uh, because
11:45of prokaryotic structures that
11:47selectively inhibit mitochondria, given
11:50the similarity of some DNA synthesis
11:53structures and some protein synthesis
11:55structures that are present in
11:58mitochondria. And it is important to
12:01take them into account because some
12:04prokaryotic inhibitors could also
12:06affect protein production or
12:08mitochondrial function. Another
12:13important indicator that is associated
12:15with the presence or incorporation of a
12:20prokaryotic structure within a
12:21eukaryotic cell is associated with the
12:26way in which mitochondrial levels or
12:29the number of mitochondria can change
12:32within a cell. We know that
12:34mitochondria are not fixed within the
12:36cell, they have different numbers and
12:38that number is associated with the
12:40energy demand of the cell. That is, the
12:43cell can change the number of
12:45mitochondria given fission mechanisms,
12:48that is, dividing a structure to
12:50generate two mitochondrial structures
12:53or fusion can form a larger
12:55mitochondrial structure from two small
12:57mitochondria. This determines a very
13:00relevant mitochondrial dynamic
13:03associated with the production levels
13:06and also associated with the recovery
13:09of mitochondria, since mitochondrial
13:11dendritic cells have less possibility
13:14of repairing themselves, given that
13:17there are mechanisms in which
13:19mitochondria can enter into dysfunction
13:25or oxidative events. The mechanisms for
13:29recovering damaged mitochondria are
13:32associated with fusion events and
13:34trying to rebuild their structure, not
13:37only of DNA, but also of proteins and
13:39membrane. So, there is several
13:46evidences that support the idea of
13:49symbiotic. Naked circular DNA is not
13:53surrounded by an envelope like histones
13:56and the complex structure for gene
13:59expression regulation that we possess
14:02in the case of nuclear DNA. It has
14:06exceptions to the nuclear genetic code,
14:09it has a higher mutation rate and at
14:11the membrane level it has a double
14:13membrane structure forming myosomes or
14:16cristae. Okay. At the ribosomal level,
14:22it presents a lower density of
14:24ribosomes, as well as inhibition by
14:27molecules that are capable of
14:29inhibiting synthesis at the level of
14:32the prokaryotic organisms. And finally,
14:37the fusion and fission mechanism
14:39associated with the change or the form
14:42of modification of the number of
14:44mitochondria. Speaking of this idea of
14:49fission, we can know that damaged
14:51mitochondria enter a system of trying
14:57to recover by fusion where they can
15:00reincorporate new DNA and new proteins
15:03into the membrane structure given by
15:06the membrane or the association with
15:09other proteins that control fusion
15:12events. Furthermore, we know that a
15:16damaged mitochondrion that cannot be
15:18recovered will be fragmented into small
15:21mitochondria that are marked with
15:23accessory proteins, some associated
15:25with the binding of mitochondrial
15:27membrane proteins and the recruitment
15:29of specific structures or specific
15:31proteins associated with the formation
15:34of this autophagosome or autophagophore
15:36. We have seen this structure when we
15:39described the degradation of
15:41cytoplasmic components. In
15:45macroautophagy, we had mentioned at
15:47that time that the selective system for
15:49the degradation of damaged mitochondria
15:52was called mitophagy, because it is the
15:55formation of an autophagophore
15:57structure around a damaged
15:58mitochondrion that has been signaled as
16:01damaged, and the incorporation, the
16:03incorporation of this autophagosome
16:06structure later with the lysosome to
16:08degrade all mitochondrial components.
16:13Furthermore, we know that mitochondria
16:16play a key role in apoptosis, since
16:18they are an important component in the
16:21signaling of the intrinsic pathway with
16:23the release of cytochrome C from the
16:26intermembrane space of the mitochondria
16:28. We will see this later when we look
16:33at cancer and apoptosis itself and when
16:36we understand how specific signaling on
16:39the outer membrane of the mitochondria
16:41can cause the cytochrome C component to
16:44be released into the cytosolic space
16:47and that will favor the signaling of
16:50the specific pathways that carry out
16:53the apoptosis process. We have to
16:59understand that mitochondrial DNA only
17:02codes for 13 proteins that will
17:05function in the mitochondria. But we
17:10know that there are many more proteins
17:12that fulfill an important function
17:14within the mitochondria, fulfilling
17:17important functions in the structure of
17:19mitochondrial membranes and in the
17:21intermembrane space. We know that all
17:25of these other proteins not encoded by
17:30mitochondrial DNA are present or
17:33encoded in nuclear DNA. So, we have to
17:37understand that there is a pathway for
17:40the synthesis of nuclear-encoded
17:42proteins that are going to be sent to
17:44the mitochondria. And so we understand
17:47that these proteins are mainly produced
17:49on free ribosomes and these proteins on
17:52free ribosomes are going to have to be
17:54incorporated into the mitochondria. For
17:56this to happen, there are specific
17:59chaperones, such as cytosolic HCP70,
18:01which maintain their unfolded structure
18:04because if they fold they will not be
18:07able to pass through these
18:09translocators or translocons, and then
18:11they present them to the external
18:14translocator of the mitochondria, the
18:16TOM, and they can pass, through an
18:19expenditure of ATP, to the internal
18:21translocator and be extracted through
18:27the translocators by specific
18:28chaperones that, with the expenditure
18:30of ATP, internalize them, now
18:31presenting them to the mitochondrial
18:37HSP60 chaperones, which will fold this
18:39protein specifically so that it
18:41fulfills a function within the matrix.
18:46We also know that there are proteins
18:48that will have to be incorporated into
18:50the intramitochondrial matrix and for
18:52that there are hydrophobic portions.
18:56And then these proteins with their
18:57hydrophobic portion can be translocated
18:59directly to the internal membrane. And
19:01there are also proteins, as we have
19:04mentioned, different proteins that can
19:07be directly internalized into the
19:09matrix and then presented in the
19:11intermembrane space through some pores
19:14or translocators and remain directly
19:17from the internal translocator within
19:20the intermembrane space. So, it is
19:23important to understand that different
19:25nuclear-encoded proteins can have a
19:28targeting pathway to the mitochondria,
19:30involving cytosolic chaperones,
19:32involving mitochondrial membrane
19:35translocators and involving
19:36mitochondrial chaperones. Now we have
19:45to understand that, if we want to
19:48locate proteins, if we want to
19:50understand the functioning of
19:51mitochondrial proteins, if we want to
19:54do some study associated with the
19:56functionality of a mitochondrial
19:58protein that may be functioning well or
20:01poorly, we may have to, uh, perform
20:03fractionation techniques to be able to
20:06isolate and run a Western blood,
20:09identify the protein or be able to
20:10isolate it and be able to do a
20:12functional study of these proteins. So,
20:15mitochondria or mitochondrial
20:17components can be isolated using this
20:19subcellular fractionation technique.
20:23And, as we have seen in the techniques
20:25section, subcellular fractionation
20:27involves trying to somehow separate the
20:28components by density, by different
20:30weight. To do this, we need to be able
20:34to isolate the components. So, what we
20:37do is this: starting from a tissue,
20:40from a patient sample, or from cells
20:42that were grown in a culture, we
20:45prepare a homogenate; that is, we break
20:48the external membranes, or the plasma
20:50membranes, to have all the components
20:53of the cell in a solution. As we can
20:57see here, the nuclei are in green, the
21:00synaptic vesicles are in dots, and we
21:03also have the mitochondria, which in
21:06this case are going to be the fuchsia
21:12dots. And then, by means of
21:16differential centrifugations, we can
21:18separate the different components by
21:20their weight, by their density. So, if
21:24we do a centrifugation or a low density
21:26, what we are going to do is that only
21:28the largest ones fall and the rest
21:30remain in solution. So, in this way we
21:33can separate the nuclei that have a
21:35high density, large membrane components
21:38, and in the first precipitate and keep
21:41, in this case, the mitochondria still
21:44in solution. We can separate the
21:48solution from the supernatant, keep
21:51that supernatant and discard or use in
21:54a Western blot separately what we can
21:56resuspend as the precipitant where the
21:59nuclei are. If we now do a slightly
22:04faster centrifugation with this
22:06supernatant, we can pellet or
22:08precipitate, in this case, components
22:11such as mitochondria, components such
22:14as lysosomes and peroxisomes and have
22:16them and separate them now from the
22:19homogenate, where the smaller vesicles,
22:21synaptic vesicles, endocytic vesicles
22:24and the components of the cytoplasm
22:27will remain. In this fraction, in this
22:30precipitate or pellet, we are going to
22:32have the mitochondrial fraction. Yes,
22:35we can continue separating these
22:36components, but since we are talking
22:38about mitochondria, we are going to
22:40keep this precipitate and the good
22:41thing is that we can use this
22:42precipitate, okay? And from this
22:46precipitate obtain the mitochondria and
22:49perform different assays within this
22:52precipitate enriched in mitochondria.
22:57We can measure transport through the
22:59membrane, activity of membrane proteins
23:00, energy production. If we give it the
23:04components, we can continue the
23:06fractionation processes. So, we can use
23:09mild, non-ionic detergents, which will
23:12only break down the outer membrane,
23:14which has different lipid components,
23:16which is the inner membrane, as I
23:18mentioned. And then we can separate the
23:21components of the intermembrane space
23:23from the components of the matrix. And
23:26then separate the membranes and the
23:28components of the intermembrane space
23:30and separate the matrix. Later, we can
23:32break this membrane and separate
23:34components of the inner membrane and
23:37the matrix, and thus be able to have
23:39each of the components of the
23:41mitochondrial fractionation in order to
23:44use them and determine, well, which are
23:46the important parts of the
23:48mitochondrial functionality for energy
23:50production, for calcium storage, for
23:53the production of steroids, all the
23:55mitochondrial functions that we are
23:57going to review now. So, if we take
24:01into account the main mitochondrial
24:03functions, the main one we could say is
24:06energy, the synthesis of ATP; but we
24:09also know that mitochondria are
24:11important for calcium storage, for the
24:14production, modification of molecules
24:16from lipid molecules and the production
24:19of steroid hormones for the synthesis
24:24of some amino acids. And what I had
24:28mentioned for the participation in
24:30apoptosis signaling, mitochondria are
24:32very important and we will see that
24:35later. Let's quickly go through the
24:41synthesis or cellular metabolism
24:44pathway associated with carbohydrate
24:46catabolism. This is something you have
24:50from the CC. I'll quickly review it. We
24:53don't need you to learn the names of
24:56each of the enzymes, but we just need
24:58you to have an idea of the synthesis
25:01mechanisms and what happens when the
25:03synthesis components associated with
25:06energy production become disorganized
25:09or destructured. So we know that,
25:12starting from a carbohydrate,
25:14glycolysis occurs in the cytoplasm,
25:16which is the conversion of glucose to
25:18pyrobate, which is the molecule that is
25:21going to be internalized within the
25:23mitochondria to, how do you say it?,be
25:29the food for oxidative carboxylation,
25:32the Crep cycle and, later, the electron
25:34transport chain and oxidative
25:37phosphorylation. So, this is glycolysis
25:41. We know that as a result of
25:42glycolysis we can obtain two ATP
25:44molecules and from them enter the
25:49mechanism of carbohydrate reduction
25:52into energy. However, these mechanisms
25:56are not efficient and we have to, or
25:58the cell given this, endosymbiosis has
26:00generated more efficient mechanisms for
26:02energy production. Thus, there exist
26:15various coenzymes that function as the
26:18early acceptors of the electrons in
26:20this process. And we are going to have
26:24these molecules, NAD in oxidized form
26:26or NAD H in reduced form, which are
26:29very important because they are going
26:31to be the molecules that are going to
26:34be produced in these cycles, of CREBS,
26:36in which these molecules will later
26:39allow a transfer of energy from, uh,
26:44the breakdown of this, in this reduced
26:47form and the transfer of electrons to
26:49the components of the inner membrane of
26:52the mitochondria. So, we know that the
26:57decarboxylation of pyrubate forms this
27:00acetyl-CoA, which is going to be the
27:05molecule that is going to be introduced
27:07into the Creps cycle. This is a cycle
27:10where it is fed with acetyl-CoA and, in
27:13each step of modification of this
27:16carbon structure, reduced molecules of
27:19NAD H and also of FAD H2 are going to
27:22be produced that are going to later
27:25allow it to approach the component, uh,
27:28complex one, sorry, of the electron
27:31transfer chain and, by breaking this
27:34association, uh, and, electrons are
27:38going to be transferred within this
27:40complex that are going to allow or are
27:42going to be used as energy to transfer
27:44protons to the intermembrane space.
27:47These same electrons are going to be
27:50transferred through coenzyme Q and then
27:53taken to complex uh three of the
27:56transfer chain. In turn, that energy is
28:00going to allow this complex to transfer
28:02another proton to the intermembrane
28:04space. Then it will be transferred to
28:07cytochrome C and complex four of the
28:09chain that will allow it to
28:11subsequently associate with an oxygen
28:13molecule and form water, okay? Use the
28:17energy between an oxygen molecule and
28:20two hydrogen molecules to form water.
28:23And that energy will also be used by
28:25this complex to transport another
28:27proton in the intermembrane space. This
28:30will generate a fairly high proton
28:32gradient within the intermembrane space
28:34. Okay? We have here another example of
28:38another scheme that you can find in
28:43another book. Again, the reduced
28:46molecule transmitting the energy that
28:49allows the passage of protons, enzyme Q
28:52, complex 3, cytochrome C and complex 4
28:55, both, all producing a transfer of
28:58protons to the intermembrane space that
29:01will subsequently be used in oxidative
29:04phosphorylation. What happens here is
29:08that this gradient in the ATP synthase
29:17complex will be utilized for the
29:19abundant production of a large number
29:21of ATP molecules throughout the process
29:24. So, in this slide we see how that
29:32gradient generated by the transfer of
29:35protons to the intermembrane space is
29:38used by this ATP synase, okay? That in
29:42the passage of protons through this
29:45pump that has a twist, it uses ADP plus
29:49phosphate to generate ATP. It is
29:54important to understand that the
29:56gradient is necessary for the twist of
29:59this machinery to occur in one
30:01direction for the production of ATP
30:03with the use of ADP plus phosphate. In
30:08conditions where this gradient is
30:11broken or the membrane becomes more
30:14permeable breaking the proton gradient,
30:18this can work in the opposite direction
30:22and in any case use ATP to spend it and
30:26in the form of breaking phosphates and
30:29ADP. So, it is very important that in
30:33the mitochondria there is a balance in
30:36the production of, uh, proton transfer
30:39to the intermembrane space that favors
30:42or sustains this gradient for the
30:44normal production of ATP. We know that
30:50we can enter the production cycle of
30:53chrbs or acetylcoa through fatty acids.
30:57We saw the one about sugars and we know
31:00that fatty acids can be internalized
31:03into the mitochondria and in the beta
31:08oxidation of fatty acids in the
31:10mitochondrial matrix. We can now
31:13generate acetyl-CoA molecules that will
31:15subsequently be used in the Krebs cycle
31:20, which will in turn be utilized to
31:22increase the overall production of
31:23energy within the cellular system. Well
31:27, we already saw that. It is important
31:32to note that, well, we know that from
31:34mutations in mitochondrial DNA we can
31:37generate imbalances in energy
31:39production. However, not all
31:41mitochondrial disorders are inherited
31:43from mitochondria. We know that many of
31:46the proteins in mitochondria can be
31:48encoded in the nuclear genome and so it
31:51will be very different. Although the
31:55mitochondrial dysfunction phenotype is
31:58similar whether the mutation occurs in
32:00a mitochondrial-encoded protein or a
32:02nuclear-encoded protein, the
32:08inheritance mechanism depending on each
32:11of the mutations will be very different
32:13in one case or the other. So, we have
32:17to understand that mitochondrial
32:20inheritance occurs through the maternal
32:23line, since the oocyte is the one that
32:27supplies the mitochondria for the
32:30generation of the new individual or new
32:34organism, and the sperm will only
32:37incorporate or secrete, in this case,
32:40the cellular DNA. So, this
32:46fertilization process ensures that the
32:54mitochondria that are transferred from
32:56one generation to the next are of
32:59maternal origin, and this will generate
33:01a characteristic that can be identified
33:04in family trees, where the genes
33:06encoded by the mitochondrial genome
33:09with mutation or inheritance patterns
33:12are solely maternal. Where two
33:16individuals from the same family, a
33:18male who has an original mutation in
33:21mitochondrial DNA will not transfer
33:24this alteration to his offspring,
33:27whether female or male. However, a
33:31woman with mutations in mitochondrial
33:34DNA can transfer it to all individuals
33:39in her offspring. We must also
33:43understand, and we have mentioned this,
33:46that mitochondrial DNA is polyploid,
33:48that is, a mitochondrion has several
33:51copies of this circular DNA. So, we
33:55lose within this presence of a mutation
33:58within mitochondrial DNA, the idea of
34:00dominance or recessivity. Okay, we do
34:04not take this into account and we are
34:06going to start talking about a
34:08variability of expression in phenomena
34:10that are associated with a concept that
34:13is heteroplasmy. And heteroplasmy is a
34:16concept associated with the different
34:19mitochondrial entities that can exist
34:22within a cell. We can understand that a
34:26cell has within this cell a cell with
34:29normal functioning, all its
34:31mitochondria functioning normally or a
34:33mitochondrion, a damaged cell with all
34:36its mitochondria functioning in a
34:38damaged way or dysfunctional in this
34:41case. So, these would be two examples
34:45of homoplasmy. This cell has all its
34:49mitochondria healthy. This cell has all
34:52its mitochondria dysfunctional. However
34:56, we can find and in fact we find many
35:00events of cells that have different
35:03degrees of forgiveness cells, of
35:07mitochondria that are functioning
35:10normally or functioning abnormally. And
35:15so we consider heteroplasmy when
35:17mitochondria with damaged DNA and
35:19mitochondria with normal DNA coexist
35:22within the same cell. So, depending on
35:27the degree of damage to this cell, we
35:29can understand that these cells are
35:31going to be functioning more
35:33dysfunctionally than these cells that
35:35have a greater degree of normal
35:37mitochondria. So, we can now use two
35:43concepts more associated with
35:45heteroplasmy, which are replicative
35:48segregation and bottleneck. So, if we
35:53understand that this primordial cell,
35:56which has a coexistence, a heteroplasmy
35:58of cells, normal mitochondria and
36:00dysfunctional mitochondria, is going to
36:03begin cell division processes in which
36:05it can segregate, in this replication,
36:07differentially the number of healthy
36:10mitochondria to the number of damaged
36:12mitochondria. Why does this occur?
36:16Because if we look at it in a simple
36:18system in which we have to understand
36:20that the mitochondria that we have in
36:23this case are mixed into different
36:25cells, if we make this idea of a
36:27bottleneck where we are going to
36:29segregate some mitochondria through a
36:31small tube, a different number of
36:34mitochondria will pass to one cell or
36:36the other, both normal mitochondria and
36:39affected mitochondria. And so in this
36:43case we can have different cellular
36:49components in which the number of
36:51mitochondria that function normally or
36:54the number of damaged mitochondria due
36:56to a specific mutation in the
36:58mitochondrial DNA is different. And
37:02given this process of, uh, uh, how do
37:05you say segregation, we can understand
37:07that, uh, it is not going to be the
37:09same if this is an oocyte that is going
37:12to be fertilized by a normal sperm, or
37:14this is going to be an oocyte that is
37:16going to be fertilized by another
37:18normal sperm. And so, the number of
37:22mitochondria or the severity of the
37:24disease in this specific case can be
37:26much higher than what we see in this
37:29individual being generated. So, when we
37:33talk about mitochondrial diseases, we
37:37generally focus on observing specific
37:43tissues that are altered or
37:46dysfunctional when we have a
37:48coexistence of healthy and damaged
37:51mitochondria and normal and
37:53dysfunctional mitochondria. We are not
37:56going to say healthy mitochondria, we
37:58cannot say that. Okay? So, when we
38:01consider and observe human tissues, we
38:05see that those with a high energy
38:08demand are generally the ones that
38:12experience a significant affectation in
38:16their functioning, given that they
38:19require a specific number of normal
38:23mitochondria to ensure the proper
38:27production of energy, in the form of
38:29ATP. So, we begin to talk about an
38:34energy threshold indicator capable of
38:36determining the coexistence of cells
38:39with functional mitochondria and
38:41dysfunctional mitochondria that are
38:44capable of sustaining a threshold
38:46energy level. So, given this
38:51segregation phenomenon, we can
38:53understand that if in this segregation
38:56we have cells that have few
38:58dysfunctional mitochondria, they can
39:05sustain the energy threshold; and when
39:08that number of dysfunctional
39:09mitochondria increases, that energy
39:11threshold cannot be maintained and that
39:13is when the appearance of a phenotype
39:16begins to be seen. So, this degree of
39:19heteroplasmy is now associated with the
39:22threshold effect and then determines
39:25that if there are cells with a high
39:27component of dysfunctional mitochondria
39:30, we will begin to observe cellular
39:32phenotypes that can later be translated
39:35into the patient's clinical phenotype.
39:42An example to observe some diseases of
39:44mitochondrial inheritance is Lever's
39:47hereditary optic neuropathy, which is
39:50mainly observed by an affectation in
39:52the visual field as a consequence of an
39:55injury or alteration in the optic nerve
39:58. These cells that form the optic nerve
40:02, these ganglion neuron cells, have a
40:04defined projection from the optic nerve
40:06to the visual cortex, which makes them
40:08cells with a high energy demand.
40:12Because these are cells with high
40:14energy demands, they must perform
40:16significant transport along these axons
40:19, which are quite large; therefore, if
40:22mutations exist in mitochondrial coding
40:25proteins that alter the production of
40:28proteins within the mitochondria, this
40:31will lead to dysfunctional mitochondria
40:33. Consequently, depending on the
40:36specific degree of heteroplasmy, one
40:37can observe significant phenotypes that
40:38are associated with this particular
40:40disease. And what we will observe in
40:42this disease is that there is, at the
40:44level of maternal transfer to the
40:49offspring, a phenotype of, uh, a mainly
40:53maternal transmission associated with
40:57mutations in mitochondrial DNA that
41:00sustain the dense patterns. So, we come
41:06to the end of this first part of, uh,
41:09the class on nonclassical inheritance,
41:14where we focus mainly on the
41:16mitochondria. I recommend that if you
41:19have time, you can quickly continue
41:21with the non-classical part two, where
41:23we will continue with the expansion of
41:25triplets and the imprint part.

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