Fasting and Overeating - How you Change your Mitochondria. [Study 32]

hi hello welcome to physionic if you're not familiar with who i am my name's nick i'm a phd candidate in molecular medicine i work in a cell biology lab where we actually study the topic that i'm going to be discussing today which is mitochondria not necessarily well actually the when i entered the lab from with my metabolism background i did end up doing a project that looked at nutrition or really kind of the cellular state of nutrition so i'm going to be presenting some information from a scientific review from the journal of cell metabolism which

is one of the gold standards for research and i'm going to be discussing essentially or answering a few different questions so how mitochondria respond so cell energy production and changing their shape to nutrition overload as well as starvation which kind of synonymous with like fasting in this situation as well as why mitochondria change their behavior and i'm saying behavior quote unquote it's not like mitochondria think about these things these are things that just happen on a biochemical level within the cells that cause changes i'll be explaining what those biochemical things are that lead to this

change in quote-unquote behavior from mitochondria i just got done reading a grant for my lab it took me about four or five hours to get through it it's almost 20 pages long and essentially what a grant is is that it allows us to apply for more money to continue the work that we do i think last year i released a video on a complex paper that we released in the journal of cell biology i want to say uh and or maybe it was jbc i don't know it doesn't matter where we discovered a new form

of autophagy when we knock out a particular protein that is involved in autophagy known as parkin but now we're shifting our focus towards some of some other areas i won't go into the details of exactly what but i'm taking my metabolism background and kind of integrating it into my project so i was kind of excited to to hear some of the things that were some of the things that we're proposing some of the areas that we've been going down and i think i think my project is going to be really interesting so hopefully one day

when i well hopefully when i do defend hopefully i'll be able to kind of distill that or concentrate all of that information uh for you guys so you guys can get some first-hand information from uh the the research that i am specifically on beyond what i've already presented from last year but without further ado let's go ahead and jump into this video and we will break this down so looking at how nutrition affects mitochondria i will have probably two videos on this because i'm going to have one which is this one explaining the mechanisms what

happens etc etc but then the second video is going to be discussing diabetes and obesity or you know how gaining weight affects these processes and some of the negatives and some of the compensatory mechanisms that our bodies different tissues cells within our tissues make but i digress so the question that we're examining as i mentioned is how do mitochondria respond to our nutrition it's a really basic way of uh going about things and it comes from this cell metabolism review which i said which i mentioned is kind of the gold standard or one of the

gold standard i mean step cell the the journal cell is right up there with uh nature and potentially science as well so those three journals are kind of the top tier and cell metabolism is kind of a sub journal within cell it's also extremely highly rated and this is a little bit older review it's from about seven years ago eight years ago uh mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure um so i'm going to break all of this down for you all right so mitochondria behavior i'm going to discuss two different

aspects of mitochondrial behavior so one of them is the change or the the change in what's known as the morphology so we've got our mitochondrion here and what it can do is it can split apart it can fragment it can undergo what's known as fission and if you've been following physionic for a while you you've maybe seen me cover this before because well it's it's an important part of mitochondrial morphology so this splitting apart leads to a single mitochondrion splitting into two mitochondria and these tend to be a lot smaller and i'll discuss a little

bit of why that might be the case in this scenario but there are a number of different reasons why this would occur the second scenario is that you get two mitochondrion that will fuse together and create an elongated or just a larger mitochondria doesn't have to be elongated but what we're going to be looking at is elongated mitochondria as you'll see and i'll actually show you some real images of what this stuff looks like so this is morphology changes in mitochondria so behavior of mitochondria can change by the actual shape of the mitochondrion another way

however and i've got this dividing line here is that one scenario leads to a reduced level of atp which is adenosine triphosphate which is cell energy production and another another scenario creates a substantial amount of cell energy and we're going to figure out which scenario belongs to which and then why there's this distinction between the two why is this there this change in atp generation why is the mitochondrial behavior changed in such a way that in one scenario you have increases in cell energy production and one you have decreases in cell energy production so a

lot of this is influenced all within the context of what we're talking about a lot of this is influenced by two things so one is the supply of nutrients so if that's blood sugar or sugar in general carbohydrates or fats so either one of those and yes amino acids also contribute ketones contribute all that stuff contributes but i usually try to distill it down to the two major ones which is carbohydrates and fats so nutrients i'll explain this in a little more detail in just a second but nutrient how much nutrient availability is there around

the cell than in the cell and then that can then enter the mitochondrion so those three scenarios outside of the cell so in the bloodstream in the interstitial fluid then entering the cell so it's not in the mitochondria but it's in the cell and then third is when it's actually in the mitochondria and the second effector the the second component of this equation is not only the supply but also the demand so cell energy demand by literally every single process within the cell requires some level of energy if that's atp it doesn't have to be

atp it can be gtp as another example and there are some other really tiny fractions that also belong to other areas as well but atp and gtp are the major ones we're going to be focused on atp because that is the major one so cell energy in the form of atp is then consumed by many like thousands and thousands of enzymes within the cell so if your atp supply drops then that means these enzymes can't function as well or if the atp levels are elevated then you do have enough atp to function allow these enzymes

to function so is the draw is the demand for energy by these cell processes also has an impact on mitochondrial morphology now to get a little bit more into details with this and i'll show you some more images of this but nutrients enter the mitochondrion and then there they go undergo this process known as the tca cycle you may have heard of it as the krebs cycle but the tca cycle as i've got it labeled here you don't need to know all these enzymes but you have fats and sugars carbohydrates that then get converted to

acetyl-coa now this molecule acetyl-coa goes through this cycle quote-unquote cycle and as it's going through this cycle what happens is you get the generation of new molecules and the two major molecules i guess i'll mention three major molecules that i want you to pay attention to is with the introduction of fat with the introduction of carbohydrates in if for anybody that's interested that knows about cell biology metabolism i'll say in an aerobic environment if you don't know about that don't worry about it for this at this moment but the these enter the mitochondrion you get

this generation of sealcoat the rotation through this tca cycle and as that happens it produces these other molecules like nadh is one of them fadh is the second one and the third one just uh just to throw it in here is also the generation of atp technically i believe you also get the generation of gtp but they don't show it here but for now just know the big ones are nadh and fadh get formed when this acetyl coa goes through this cycle all right so there you go there's an explanation of the the supply and

the demand and how the supply gets turned into these different intermediate molecules and those will come back in just a second so let's discuss now nutrition overload how does nutrition overload the over consumption or the the elevated amount of fats and glucose etc being present how does that affect mitochondria well let's discuss the morphology first the morphology is what happens and as i promised that these are these are actual images of what happens we've got our mitochondrion and what happens is that it fragments so we get smaller mitochondrion that end up being formed out of

a single mitochondrion so it splits into one or maybe multiple other mitochondria so and you can see that in this image here so this is uh before this fission occurs this fragmentation occurs and you can see that this is all fluorescent so it's all fluorescent in green so all the green is mitochondria the blue is the nucleus you don't have to worry about that just look at the green and you'll notice that you know if you kind of trace these with your eyes you can see that they're considerably longer they have some length to them

at least and this is kind of an intermediate state as well as you'll notice in a little bit but the point is if you compare this image to this image suddenly they're much rounder they're much tinier they're not as elongated as they are here so does that mean that you have lost mitochondria not necessarily all it means is that these mitochondria have changed their shape from a larger mitochondrion to a smaller mitochondrion okay so to explain a little bit more on on the energy aspects and why this might happen with fragmentation what not we have

to look inside the mitochondria so we're looking inside a single mitochondrion as you can see up here on the left and we're zooming into the inner membrane so there's the outer membrane then the inner membrane and there's a space between the two membranes this is called the inter membrane space so we don't have the outer membrane shown here just because i didn't want to i deleted a few different things because they just didn't add to the to the they just add more to look at and they just end up confusing so just know that there's

a membrane up here which is also part of the mitochondrion and it holds the rest of the cell away from the inside of the mitochondrion which is here okay so and here you might recognize yet again this nadh and fadh so those do come from the tca cycle and this is known as the electron transport chain so these are proteins and i promise there's a point to understanding this so these proteins are integrated into the inner membrane of the mitochondrion so with these electron transport chain proteins what they do is they interact with this first

one complex one that's the name of this one complex one it has a more a fancier name as well uh but like oxido reductase but complex one for sim for simplicity's sake because this is already going to get to really uh into the woods but complex one will then interact with nadh and essentially remove electrons so that's where we get these two electrons right here and those electrons get pushed or get moved from complex 1 to coq and then we'll get delivered to complex 3 and then cytochrome c and then complex 4. and the same

similar thing will happen with fadh fadh w will interact with complex 2 and generate more electrons which will also go through this process and ultimately the the end fate of these electrons is that they end up interacting with oxygens and hydrogens in creating h2o so known as metabolic water you don't that's not that important what is important however and what i will be pointing out is that as these electrons are flowing from from complex to complex to complex going through until complex four where it's finally converted to water there is a pumping of hydrogen or

protons specifically protons from the matrix or the very intersection of the mitochondrion to this inter membrane space now why is that important because protons are positively charged so what we want is there's a negative charge we want a membrane potential so a negative charge inside the mitochondrion and we want a more positive charge or a more acidic environment in the inter-membrane space here is where we keep most of the protons so the mitochondrion keeps most of the protons and then what happens so you can see that the arrows are all pointing out of the matrix

and that's powered by these electrons that allow for these protons to be pumped back out of the matrix into the intermembrane space now as this starts to increase with more and more protons this protein right here the atp synthase will then start rotating and the way that it rotates is kind of like a uh like a a mill have you ever seen a water kind of spill over a mill and the wheel starts to turn that's exactly what's happening here that the protons from this high gradient the high amount of protons up here will start

to spill through this atp synthase rotating the atp synthase and in doing so the consequence the product is the generation of atp or cellular energy so in this direction three times over protons are moving out of the matrix of the inside of the mitochondria the very inner parts parts of the mitochondrion and in this situation you have protons then moving back into so it's a constant cycle going back and forth so it has to be in kind of uh i don't want to call it equilibrium but it has to be continuously moving uh back and

forth out then in out then in continuously so that's what would normally happen and we get the generation of atp as a result so you have to have this balance of do you have enough product do you have enough supply and do you have enough demand of on both sides so this is the demand so the atp would then be consumed by all the different cellular processes i was talking about earlier and then for the supply do you have enough nadh and fadh to actually run this cycle all right so now remember we're talking about

a nutrient overload situation now if supply is so great and demand is not great enough so demand is small and supply supplies high then you have a high degree of nadh you have high amounts of fadh and they go through the same process right donating electrons it's going through this electron transport chain but the problem is that because you're getting so much pumping of hydrogen out and you're not getting enough of this drive to generate atp because you have enough atp you don't need more atp so you get a lot of protons that build up

out here but there's no drive through a metabolic demand right here through these reactions that would happen enzymatic reactions and whatnot so the protons are staying up here because there's only a small amount still coming through here to generate atp relative to the amount of supply that there is so as such what happens is you have a proton you have protons and electrons that start to leak so instead of staying where they should be going where they they normally would be for example the electrons instead of being pushed from one complex to another complex they

end up slipping meaning that there's so much pressure building up kind of if you want to think about like chemical pressure uh think of it like a like a hose almost that the water is coming in this way and the opening is only so big but the pressure keeps building on this side eventually wherever there are weaknesses in these complexes you're going to get slipping of these electrons they're going to start bouncing all over the place instead of going to their respective spot because the respective spot is taken by another electron because there's no pulling

there's no there's no release through the atp synthase so these electrons start to slip kind of like a hose that has a weak point and you start having a bit of water that starts poking out of the side and then another leak coming out of another side and it builds and builds and builds to the point where all these electrons are starting to to freely be released from this electron transport chain or not go to the electron transport chain and it starts generating reactive oxygen species which if you've been following physionic for a while again

you know the different effects that ross can have ros can have however there's a lot more that i can talk about ros that i won't go into in this situation but if you have an overabundant amount of ros then these molecules will then start damaging all the other molecules around them and that is known as an overarching term as oxidative stress so that is the situation when you have an oversupply of nutrition the supply is really high and this seems to lead to this fragmentation of mitochondria and in certain tissues there's something unique that happens

now one of those tissues would be for example brown fat cells and i'm gonna i'm gonna tell you half the story now and i'm gonna leave half the story for the next episode but related to diabetes and related to obesity but in a high nutrition overload situation high fat high glucose high nadh production high fadh production instead of driving this electron transport chain trying to push the atp synthase to to generate more atp even though there's no demand on the back end so instead what happens is there's this as i alluded to earlier a leak

in hydrogen or protons specifically so suddenly the the mitochondria will start to generate more of these proteins that are essentially like pores they're like circles they well i don't want to call them circles it's not exactly right but there are these pores that then integrate themselves into the inner membrane and then from that point now you have this unobstructed this uninhibited release or movement of protons from the inter-membrane space back into the matrix and this is the reason why i say it's uninhibited is that it's not coupled that's a big key word that it's not

coupled to energy generation so even though the cell may not need this this this added energy it still produces this alternative pathway to speed this whole process up because at this point the process is going very slow there's a huge drive here to go go go go go go and here then we get to these sections and because this is kind of just moseying about it's it doesn't have the drive by this cellular demand that i showed you earlier right here these cell processes it's not going to be moving very quickly however then the cell

decides to introduce not again not that the cell's thinking but biochemically speaking the cell then generates more ucp or uncoupling protein sticks it in here and the protons can start bypassing the atp synthase this in effect reduces the amount of energy that is produced however it saves the mitochondrion from overproduction of reactive oxygen species so it is a it's a brilliant mechanism and this is all according to this review so a lot you know some of this is certainly speculation some of this is definitely speculation but based on the available evidence up to this point

that this then allows this to then speed up so you're burning through these nutrients you're burning through this nadh and fadh without the consequence of these reactive oxygen species being produced as you're basing this this sudden speed up based off of the proton gradient and not necessarily based off of the energy production needs that are necessary because these energy production needs have not increased but the proton gradient has been changed so that now you can smoothly go through this process hopefully that made some sense to you that we're looking at it from two different perspectives

all right so what about a low nutrition load based on what we already know and what we've seen with what happens to the morphology the actual changes in shape what would you expect to happen well if you said the opposite then you'd be right and that's what seems to happen so mitochondria will then elongate and this isn't this isn't a great image but i just kind of quick ripped it off the the internet just a quick show you that here you've got kind of your intermediate mitochondria you have some smaller ones again this is uh

through fluorescent microscopy and the the images aren't fantastic but ultimately you see that it's more puncta based meaning that you have more of these circular mitochondria you have some of the kind of generally a little bit more tubular mitochondria for sure so you have a nice mixture between the two however then when you go under a starvation media or i guess a starvation scenario and that can be something like fasting or it can be something like just low nutrition calorie deficit etc of course fasting is going to have an even greater effect then you start

having these more tubular mitochondria where they end up fusing together to form more tubular elongated mitochondria so in this scenario what happens is let me quickly throw myself back up here in this scenario what happens is that you don't have this significant drive through supply you don't have a whole lot of supply uh to to just burn through it's not like the cells or the mitochondria are just trying to burn through through their supply at this point because they have a far fewer levels of this supply of molecules fat molecules glucose molecules and therefore you

have lower amounts of nadh and fadh relatively speaking so this is what's known as coupled mitochondria so remember with the uncoupling protein it uncoupled mitochondria from energy generation but now now what happens i was just checking if i had another slide to explain this but now the demand for energy is higher than the supply and in this scenario now the mitochondria plays as kind of the middle man or middle person middle thing and what it does is it starts to couple it strongly couples the energy production to how it's going to then function so as

in let me explain a little bit more so the demand is increased substantially the supply is decreased so as a result it can't afford to build you uncoupling protein and just waste this proton gradient through these electrons it needs to use the electrons to the maximum efficiency so therefore the efficiency of mitochondria increase substantially so as such uncoupling protein does not get produced and therefore we have this coupled mitochondria that simply bases its function off of the atp generation so in this scenario unlike the other scenario the other scenario we had decreases in atp production

because the mitochondria were just spinning or functioning based off of the proton gradient in this scenario it's not as much based on the proton gradient although it's still important but more so on the energy generation so these enzymes that are not pictured need more atp therefore each electron ends up yielding doesn't does not end up slipping from the electron transport chain does not end up being used in production of ros but instead is efficiently transferred complex one complex two complex three four etc therefore allowing for an efficient pumping of protons and therefore an efficient use

of those protons then back into the matrix to generate atp to generate energy hopefully that made sense and the final thing the last thing let me get rid of my image so you can see this more clearly the last thing here is that not only one of the problems that you might be thinking to yourself maybe if you've if you've gotten to this point if you do for example fasting and you're really into autophagy and stuff one of the issues is that what if mitochondria are becoming more efficient let me cut to this real quick

if mitochondria are becoming more efficient and with fasting we see increases in autophagy which would presumably get rid of some mitochondria which is known as mitophagy why would that happen why would we have a need for mitochondria and yet we're getting rid of mitochondria well this is called selective mitophagy which i've actually had other content on as well and it turns out that that is not what happens in terms of yes autophagy may increase but the mitochondria are protected from the autophagy so here in a normal situation under normal circumstances let's say you've got a

damaged mitochondria or whatever it ends up being enveloped by the the phagosome and it will then be bound by what's known as a lysosome and the auto lysosome i believe that's the correct term auto lysosome will then destroy this mitochondria and then those components will be some of them will then be recycled for the generation of other things within the cell however because of the elongation process it's believed that this elongation process protects the mitochondria from autophagy so normally to undergo autophagy you would want the mitochondria to be smaller so this phagosome can circle around

it enclose the the mitochondrion and then end up destroying that mitochondrion however in this scenario it cannot happen because the mitochondria is far too large so this is a really cool mechanism by which you can have fasting but you can preserve your mitochondria or at least the mitochondria that need to be used or that need to be preserved in that they are not damaged all right so in conclusion mitochondria respond to let me look at my notes here real quick mitochondria respond to nutrient availability in a high nutrient available availability scenario mitochondria will fragment reduce

their energy production and if possible waste more energy meaning that they don't go through that coupling cycle of generating more atp because that would they don't have that drive to generate more ener that more atp they end up wasting it by allowing the proton gradient to move through the uncoupling protein when nutrient availability is low mitochondrial efficiency increases as more energy is produced because it can't afford to use uncoupling protein to waste the proton gradient mitochondria will also lengthen and enlarge protecting them from mitophagy which is the autophagy of mitochondria now in the next video

that i'll be discussing is how does diabetes and being overweight affect mitochondria or how do mitochondria affect these issues so i've described some of the mechanisms in this video however ultimately some of these mechanisms will end up failing in certain tissues and those tissues will then be strongly driven towards a more diabetic state or a more obesogenic state so if you're interested in that then please click on the next video and i'll teach you all about that as well and if you're not interested then thanks for stopping by up to this point and i'll catch

you in the next one have a good one see ya