Peering into the mitochondria to reveal cellular stress and disease

Peering into the mitochondria to reveal cellular stress and disease Scripps Research 21.9K subscribers Subscribe 48 Share Download Clip Save 1,295 views Nov 7, 2024 The mitochondria are well known for being cellular “powerhouses,” given their important role in energy generation. Yet, emerging research is now suggesting these organelles also play a key role as the stress-sensors for the cell. In this free Front Row lecture, Scripps Research assistant professor Danielle Grotjahn will explore how mitochondria change shape in response to different genetic and environmental stressors. By harnessing cutting-edge imaging technologies to examine mitochondria in these never-before-seen-ways, Grotjahn is revealing how these organelles can predict overall cellular health and even disease, including neurodegenerative disorders and cancer. https://www.scripps.edu/ Featured places See more information in Google Maps Scripps Research Research institute 4.2 (58) Details Transcript Transcript Search in video 0:01 well good afternoon everyone and uh welcome to the front row uh my name is 0:06 Jamie Williamson I'm a professor here at scripts and uh let me be the first to 0:11 welcome you we have quite a few people here uh in attendance and we've got another big group that's uh coming in 0:19 virtually online so welcome to everybody uh and today we get to welcome Danielle 0:25 Gran um and you know I I want to say a little bit about uh by way of production 0:30 about what she's working on but uh she's working on U mitochondria and trying to 0:36 understand their role in disease and she's using some very powerful and Cutting Edge and evolving technology uh 0:43 called electron tomography and so mitochondria are particularly important 0:48 in our bodies because they are the PowerHouse of the cell so some they're 0:54 actually kind of a furnace their their job is to be this little compartment 0:59 where you you turn glucose into ATP and uh they try to do that as efficiently as 1:06 possible but some amount of that is released as heat and so the fact that we 1:11 maintain our body temperature is in part due to this throwing off of excess heat 1:16 so they're really U you know not only fundamental to the function of the cell but to us as an organism and I'm going 1:24 to let her explain the many ways that the dysfunction of mitochondria might be involved in some some very common 1:31 diseases uh now I want to say a couple of other things um first of all there's 1:37 a it's it's our 100th anniversary so 1:44 yeah uh Ellen Browning scripts founded a set of institutes a hundred years ago 1:50 and we are the the descendant of one of those and we have a lot of sort of Centennial activities that are going on 1:56 so stay tuned in it but it's it's just a great time to reflect on how did we get 2:01 here and where are we going so it's it's been good to do that uh now I I want to 2:06 say U something about the fellows program so Danielle was one of our uh 2:13 first fellows we have this program called scripts fellows and we patterned it after a couple of other successful 2:19 programs you might have heard of Whitehead fellows at MIT Miller fellows at Berkeley but we have scripts fellows 2:25 here but but the idea is that we capture someone right out of grad uate School 2:31 typically you get your PhD and then you go do post-doctoral study somewhere and 2:36 then apply for a faculty position so what we do is create this fellow position somebody right out of graduate 2:42 school with tremendous promise and potential and we give them this mentored environment to develop their independent 2:48 program and at the at the end of that so this is a three-year position at the end of that we want to hire them onto the 2:55 faculty so I I forget what number you were number five number three number 3:00 three and and so we've had about nine or 10 fellows and I think eight have 3:07 actually joined the faculty so it's been a tremendous way to get people at at The 3:12 Cutting Edge uh and you know coming out of fantastic Labs with new things they bring it to scripts and and Dan Danielle 3:20 is the one that really set up cryoet here cryo electron tomography here at scrips so it's a great program uh and 3:27 she's off to a tremendous start so she's one of our you know young assistant professors that's you know working on building 3:33 their program so this is very much a looking at the future this this is the new thing you know I'm going to retire 3:41 someday and we need you know the Next Generation to to replace us and so Daniel's off to a fantastic start as 3:48 you'll see uh and then the last thing I want to say is something about basic 3:53 research so a lot of the front row lectures tend to focus on drug Discovery 3:59 where talking about curing diseases finding new medications and that's great but I I would say that's probably you 4:06 know somewhere between a quarter and a third of what goes on at scripts research a lot of what we do is just 4:11 basic research what does that mean mean how does stuff work the things that you 4:17 know that Danielle is going to talk about or just trying to understand mitochondrial structure and how that 4:23 structure relates to its function and sure it's important for disease but she's not making medicines she's trying 4:30 to figure out how stuff works and it's really really important that that everyone understand we have to support 4:36 basic research that's the foundation on which medical discoveries are made and 4:42 without that there can be no progress so uh before Danielle comes up I want to 4:48 say just one thing about what happens at the end so she'll give her lecture and at any time if you have a question you 4:56 can type it into the chat if you're virtual uh if if you're here save it and 5:01 then at the very end I'll come up and Danielle and I will sit here we'll have a little discussion uh I'll get fed some 5:08 questions from the virtual audience and we'll have someone just put your hand up and someone with a lightsaber will come 5:14 so that I can see you and call on you and we can try to have questions from from the audience don't be shy uh ask 5:21 ask anything you like um probably no medical advice will be given uh at this particular session but but we're happy 5:28 to have any kind of questions you'd like so I will join you at the very end um 5:34 sorry I just said all that stuff so um I'll join you back at the very end and 5:39 please let's welcome [Applause] 5:53 Danielle hello everyone it is my pleasure and honor to be presenting to 5:59 you today at our final front row lecture of 2024 I want to First acknowledge the 6:06 incredibly hard work of both Jamie and the development team for putting on this fabulous event let's give them a round 6:11 of [Applause] 6:18 applause so I'm here standing in front of you today giving you this front row lecture thanks to two incredible women 6:26 who have really influenced my life the first is my mom Julie who uh for the 6:32 first 10 years of my life it was just her and I uh she raised me as a single 6:38 mother we had an incredibly close Bond we did almost everything together and 6:44 the second woman that's very important to both of our Lives was my mom's mom a 6:49 very special lady known as grandma Pat and I'm bias of course but those 6:57 that know Grandma Pat know I'm not being hyperbolic when I say she was one of the most kind patient and loving women to 7:04 ever walk this Earth and she was the ultimate Homemaker which made for an 7:10 incredible mom and and Grandma and something that I really appreciate is 7:16 that both of these women really enabled me to be a very curious child and 7:21 allowed me to explore the natural world around me which was quite easy because I 7:27 spent a great deal of time at my grandpar parents house they had a beautiful 5 acre piece of land I would 7:33 go around exploring playing makeb believe making all sorts of stories in my head about Adventures I was going on 7:41 I would find treasures in uh the creek known as Pigeon Creek out back and even 7:47 enjoyed all of its glory in all of the seasons uh and I know some of these uh 7:53 pictures frighten us as Californians now but I promise you as a kid this was very 7:58 wonderful to have this ability to explore the nature around me and in retrospect I realized that my grandma 8:05 took a lot of inspiration from the natural world as well in her work as an artist and she had several mediums in 8:12 her art but one of my favorites mediums was that she was a very talented quilter 8:18 and she made these beautiful decorative hanging quilts which here are just a few examples I think you can appreciate 8:24 really how she took the beauty of the natural world around her that really inspired and influenced her and and this 8:31 uh was imparted on me as well and there was a pivotal moment for me that really 8:37 set me on a trajectory that led to my scientific curiosity which was that uh 8:44 for my um ninth birthday I was gifted uh a microscope kit a beginner's microscope 8:50 kit now this isn't the exact one but it's something very similar to what I received and I couldn't be more excited 8:57 I remember ripping open that pack package set setting everything up and 9:02 then performing some of my very first experiments where I would scrape the 9:07 inside of my cheek I would shmear that onto a glass slide drop some magical dye 9:14 blue dye liquid on top sandwich it in between a glass cover slip and just looking at the thing it you know it was 9:20 a little bit of a mess and it didn't look that interesting however when I looked at it underneath my new apparatus 9:28 I discovered an incredible new world a world that was completely invisible to 9:34 my naked eye but really opened up my Fascination for the microscopic world 9:40 and this was really from a young age where I gained an appreciation for the 9:45 idea that we could think about life across scales so what we mean by this is 9:51 certain things like me standing up here in front of you maybe my finger maybe 9:56 you can look down at a strand of your hair those are parts of life that we can access with our naked eye however uh 10:04 there are smaller Machinery that enable all facets of life that we aren't able 10:10 to see with our naked eye but we can see with the help of technology for example 10:16 using microscopes we can use technology that enables us to illuminate these tiny 10:23 tiny compartments that make up all of the human body and we can use uh lenses 10:28 that are not so different from the lenses you may have in your glasses to magnify these and discover entirely new 10:34 worlds and so this to me was really my journey uh to understanding and 10:40 appreciating the microscopic world that you'll see has carried me through my throughout my scientific career and even 10:47 to this day in my lab and so I was motiv motivated by this curiosity to attend uh 10:53 undergraduate at the University of Wisconsin Madison go Badgers 11:00 and uh the University of Wisconsin W Madison is an incredible Public University uh it in a lot of ways but 11:06 one of the really important ways for me was that it offers a lot of opportunities for undergraduates who have no experience working in a lab to 11:14 work in Labs that are doing cuttingedge research and I joined uh the College of agricultural and life sciences and they 11:20 had this really cool program called the honors and research program which enabled you to have access to these labs 11:27 and kind of took you throughout all your years of undergrad through working on a research program and so it was here that 11:33 I joined the lab of Francisco pagri um this picture is a very old and treasured 11:39 picture you're not um imagining things it's a little bit damaged here because it's so loved that part of the the um 11:46 picture has gotten stuck to the frame but nonetheless uh I hope you can appreciate the group and in particular 11:52 Francisco pgre who was my first mentor and really set me on a path in research 11:57 and in his lab we uh studied or we used um a fish called the zebra fish they're 12:05 these really tiny fish and what we use them for is because they produce eggs 12:11 that you can then fertilize that are transparent and why this is important from a microscopist point of view is 12:17 that it gives us access to look at all the inner workings of inside of the the cells that'll enable them to function 12:24 and so I spent several years of my undergraduate as well as a tech later 12:30 collecting freshly fertilized eggs and literally watching them divide watching 12:35 life happen before my eyes so I would uh they would go from one cell to two cell 12:41 that's the time I was taking them and running up to the microscope room and then by the time I got to the microscope I could capture pictures of them at four 12:49 cells 8 16 32 and the goal for my project was that we had this hypothesis 12:55 that the Machinery that helped them divide was also dictated the overall shape as they were developing and so I 13:02 would capture these images and I was paired up on this project with a 13:07 graduate student in the lab who was visually impaired and this was uh made for an incredible team between the two 13:14 of us because he was very gifted with numbers and computers and so what he 13:19 taught me was the value in transforming microscopy images into numbers that we 13:26 could gain u meaning from now why why is this important well quantification from 13:31 these images is important because let's face it life and biology it's a little 13:37 bit messy no two people are the same no two cells are the same but Trends do 13:42 exist and so our job as microscopists and as biologist is to figure out creative ways that we can quantify what 13:50 we're seeing in our images put them into numbers so that we could run statistics 13:55 that tell us what is due to let's say differences that might be due to a 14:01 healthy versus a disease cell versus differences that might just be due to the fact that no two cells no two people 14:08 are exactly alike and so this was really uh started my journey of another important aspect um that we still do in 14:15 my lab which is thinking of creative ways to quantify the images we have and some of my lab members that are in the 14:20 audience here might get a kick out of this that this is actually something that I drew as an undergrad and it's you could go on the look in my lab today on 14:27 the Whiteboard and you might see very similar sort of schematics there and so this led me to completing 14:34 my honors thesis at W Madison and then it came time to think about going to 14:40 graduate school and uh this whole time I had been working with a special type of microscope called a light microscope 14:47 like as like I mentioned before we use light to illuminate the Unseen World but 14:52 throughout my journey in undergrad I had learned about another type of microscope the electron microscope and what's 14:59 powerful about the electron microscope is that it enables you to look at even finer details of even smaller Machinery 15:07 of life everything down to the the compartments I'm going to talk about in a little bit mitochondria to the viruses 15:13 that can cause global pandemics to the motors that power our cells and even the 15:18 DNA that provides the blueprint for all life and so I knew for graduate school 15:24 that I wanted to go to a top tier school and I wanted to learn how to do this 15:30 electron microscopy So after talking to my network a little bit and doing some Googling of course I arrived on scripts 15:38 research as being one of the top places to to learn this and so this is why I decided to come here for a PhD now 15:45 there's lots of people that really led to scripts being a top tier place to do electromicroscopy but in particular 15:52 professors Clint Potter Bridget carer and Ron Milligan they were really Pioneers in the field and they all used 15:59 um all of them used electron microscopy in their research to study biological 16:04 Machinery but they also really fostered the development of the field into into 16:10 what we know it today as a very cuttingedge technique and they started doing this Workshop uh that would happen 16:16 at scripts and it became quite popular um where they would have people from all over the world come um different very 16:23 esteemed guests like Professor Richard Henderson who then went on to win the Nobel Prize for his contrib contribution 16:29 to a special type of electron microscopy called cry electron microscopy as well 16:34 as uh professors Bob Glazer and David daier who also made seminal contributions to the field and although 16:41 Professor daier spent most of his career in Boston we're very fortunate to have him uh be part of our La Hoya Community 16:48 here and for an electron microsopic like myself it's very special to have him even in the audience 16:53 tonight and so uh at scripts I um was studying 16:59 um a part of the cell that we can think of as like the train and the train track of the cell otherwise known as dining as 17:07 the train and microtubules as the train tracks and uh what we knew about these 17:12 is that they were very important for shuttling things around our cell which you can see here these are the the green 17:18 dots of the dining zipping around on the train tracks of the microtubules but we 17:24 didn't have a complete picture of what they look like and without a complete pi picture of what we look like we don't 17:30 really understand fully how they function and so in graduate school I used electron microscopy to transform 17:37 these Green Dots into more detailed pictures of these molecular 17:43 Transporters and in doing so I made a very important discovery which I'll show you right now it was the fact that 17:51 everyone up until this point had always thought that there was just two engines 17:56 on this train and I'm highlighting these these engine components right here but my work showed that there were indeed 18:03 four engines that were hooked up onto this and so this was a complete paradigm shift in the field for how we think 18:10 about how this transporter works and really it sort of at the the molecular 18:15 level shifted our idea that maybe they're not like trains but maybe more like supercharged chariots uh kind of 18:22 like these horer uh chariots in this uh this famous uh action scene from Ben 18:29 and so this impact of this work uh was pretty profound on the field and because 18:34 of this uh I was recognized as one of 13 recipients of the very prestigious 18:40 Harold uh M win trub award and I think I was uh one of two students to receive 18:45 this ins scripts history so this was um a very proud moment for me that I was 18:51 able to use this Cutting Edge technique to make this new discovery and this led to uh my graduation from my uh PhD 18:59 adviser Gabe Landers lab as the First Student in his lab uh to graduate and so 19:05 at this time as Jamie mentioned I was sort of thinking about what I wanted to do next and I was very excited about the 19:11 idea of starting my own lab and scripts had just started the fellows program so 19:16 I joined as the third fellow behind uh Michael bolong and Michael herb and I 19:21 knew I wanted to continue using Cutting Edge microscopes to make really impactful discoveries however in the 19:29 last few years before starting my lab several things happened that really expanded my scientific motivation and 19:36 made it a bit more personal the first was that U my grandma Pat was diagnosed 19:41 with Parkinson's disease and although this went relatively unnoticed and undetected for a while especially when I 19:48 was a graduate student uh she started to decline quite rapidly and then a few 19:53 years later my mom was diagnosed with a very aggressive uh form of brain cancer called the Gad 19:59 and so um while both of these diseases are incredibly devastating for both the 20:05 patient and uh their loved ones at the cellular level they're very different 20:10 they both affect these cells within the brain um but Parkinson's disease is 20:16 what's considered a neurodegenerative disease so it's inherently characterized by a progressive loss of cells whereas 20:24 cancer is the opposite it's characterized by an uncontrolled growth of cells within uh within whatever 20:32 region of the body in this case um my mom's brain but one unifying Factor 20:38 despite being so different are these tiny compartments that are within these cells called 20:44 mitochondria and so I realized that a key to my to my understanding these 20:50 devastating de diseases was to understand more about the mitochondria so it was at this moment that I decided 20:57 to dedicate my scientific's life work to understanding more about how mitochondria function in healthy cells 21:04 and what can go wrong in disease States so you may not think that you know 21:09 anything about mitochondria uh but Jamie already gave away something very 21:14 important uh mitochondria have the best catchphrase out of all the cellular components right say it with me 21:21 mitochondria are the PowerHouse of the cell right and this is a pretty good 21:28 catch phrase I have to say I mean it's you know it mitochondria do indeed generate energy for almost all cells in 21:35 our body but over the last few decades we've really begun to appreciate in the field that mitochondri do so many other 21:42 things in the cell so many things in fact that I don't have time in this lecture to talk about all of them but 21:50 two I want to focus on are there roles in both powering cellular life through 21:56 their role in energy production and metabolism M as well as their paradoxical or opposing Ro role in uh 22:03 triggering cell death through a pathway U that is known as 22:08 apoptosis so you can see they have very important roles in dictating whether a cell lives or dies and because of these 22:15 important roles it's probably not a surprise that in addition to neurodegenerative disease and cancer 22:21 mitac Kinder dysfunction is associated with a myriad of other diseases these are just a few of them listed up here 22:29 and so understanding uh what goes wrong in disease was really important to trying to think about ways that we could 22:35 therapeutically Target them and although mitochondria dysfunction is a Hallmark 22:40 of many of these diseases in the field we've had relatively limited success in 22:45 actually targeting the pathways that lead to mitochondria dysfunction and in my lab we propos that 22:52 this is in part because we don't understand an important part of how they function and this has to do with how 22:58 they're shaped and if we uh knew more about how they were shaped we might be able to address some of this uh in the 23:06 field so uh what is the right shape of mitochondria well up into this point 23:12 I've showed you this presented to you this very Egg Green Egg shaped looking 23:17 entity and put a label as mitochondria there so you may uh trust me that this 23:24 is how they look this is often how they're presented in the majority of of 23:29 uh high school and undergraduate biology textbooks but the reality is and if you take nothing else away from this lecture 23:35 today I want you to remember that the the reality is is mitochondria can take on many different shapes and sizes and 23:43 they're uh constantly in motion and what you're looking at here is a very beautiful time-lapse movie that was 23:50 generated by a postto in my lab Nati and uh he's harnessing a technology that's 23:56 similar to the phenomena has anyone ever SE see the bioluminescent waves off the coastline yeah so uh biologists and 24:03 researchers we've sort of harnessed aspects of that to enable us to illuminate parts of the cell that we 24:09 want to look at and so in this case you're looking at a single cell here where all of the mitochondria are lit up 24:15 and we're looking at um we're taking images every 5 seconds so I think hope you can appreciate that you know few if 24:22 not any of these mitochondria look like an egg um and so uh hopefully I've convinced you that there they're they 24:28 look quite different than even how the textbooks present them and the two main processes that dictate their shape are 24:35 the processes of fusion or the joining together of mitochondria you'll see that 24:41 happen here in this movie and uh the the opposing process is the process of 24:46 fision or the division of the mitochondria which I think happens somewhere around there and so these two 24:53 fision and fusion processes are really what dictate the the shape of the mitochondria and they're really 24:59 important for cellular and mitochondrial function and if you were to just take a snapshot of the mitochondria in the cell 25:06 like I'm showing here under normal conditions uh you get uh what I think of 25:12 as sort of this Goldilocks what we call it a network all the mitochondria in the cell and this is reflected by this 25:18 balance of these opposing fision and fusion processes so you have some big mitochondria some large ones and 25:24 everything in between but in some conditions where cell the the environments are changing 25:32 uh you can have a hyperactivation of one of these two opposing processes so for 25:37 example when there's a a limitation of nutrients within the environment uh 25:44 often times there will be an excess of the fusion pathway which leads to 25:49 mitochondria becoming super hyperconnected it's kind of like to me they look like spaghetti or Linguini all 25:56 uh within the cell and in General this is associated the shape of mitochondria is associated with more functional 26:02 mitochondria that promote cell survival however some conditions within the cell 26:08 uh can hyperactivate fision which turns the Linguini more into like a risoto and 26:15 this uh leads mitochondria to becoming more damaged or dysfunctional and by and 26:20 large this is associated with uh cell death and so while we understand and 26:27 appreciate that mitochondria our Dynamic we're still missing a lot of information 26:33 about how this happens and what it really means for the cell and so this is something that my lab is really 26:39 interested in in studying and so what we're doing is we're providing more detailed views of mitochondria even more 26:45 detailed than these images I'm showing you to try to understand this and we're harnessing technology the same 26:52 technology that's used to uh for semiconductor technology so every modern 26:57 electronic has has a semiconductor in it um and it's used and it's etched in this way using a similar device we are using 27:04 this device to etch into our cells and expose regions of the cell that have been previously um unattainable by any 27:12 other technique and we can take those thin newly exposed regions and then we 27:18 put them into our electron microscope and then while in the electron microscope we perform a microscopic CT 27:26 or MRI scan so if anyone has ever gotten one of these you know that you sit in this tube and something kind of spins 27:33 around you this is kind of similar except for this would be as if they were spinning you and the detector remain the 27:39 same uh we do a similar approach to generate all different views of our cells and the mitochondria within the 27:46 cells and then we use computational algorithms um fancy math to take all of 27:52 that information and reconstruct it into a three-dimensional representation of 27:57 the mitochondria within the cellular environment not unsimilar to a lot of the technology and algorithms that are 28:03 used actually in the the Medical Imaging community and because scripts research 28:08 is always at the Forefront of cutting Ed te Cutting Edge technology they were one 28:13 of the first in the US to really make an investment in this technology that enables us to dive into cells and view 28:20 mitochondria in this way and in fact when I started my lab in 2019 I was uh 28:26 among one of the the few researchers the few dozen researchers in the world that had the expertise and the access to this 28:32 technology and so we really took advantage of this to to look at mitochondria in different ways and I'm 28:39 just going to highlight for you some of the different ways that we're looking at at 28:44 mitochondria so the first thing we wanted to ask is is there anything different on the very detailed 28:50 microscopic level between these Linguini mitochondria and the risotto mitochondria and in particular we wanted 28:58 to know something special about these structures that I've highlighted here which are the barriers um to uh between 29:05 the inside of the mitochondria and the rest of the environment we call these barriers in biology membranes and 29:11 mitochondria are unique and that they have two membranes which we call the outer membrane and the inner membrane 29:18 now while the outer membrane is quite smooth the inner membrane fold forms this Labyrinth of folds that we call 29:25 chiste and the shape of these Crist is really important because the shape enables them to function efficiently and 29:32 so we wanted to ask is there anything different about these special folds uh 29:37 between the Linguini and the risotto mitochondria and so here's an example of 29:42 what our data looks like to me it's quite beautiful and I can pick out the mitochondria in 5 seconds but I 29:49 appreciate that to most in the audience it's just like a weird Jackson poock painting uh so in order to make it a 29:56 little bit more digestible to us what we often do is we make these um three-dimensional models that we call 30:02 segmentations where we only take out the piece that we care about in this case the membranes and I'm showing the outer 30:08 membrane in purple and the inner membrane in pink and I hope now we're all becoming uh microscopists observers 30:17 um we can describe I'll go first uh what these chiste look like and to us what we thought they look like were kind of like 30:23 rungs on a ladder you can almost imagine uh the temptation of wanting to just like scale up one of these as if you're 30:30 scaling your roof uh to to repair it and so these were what these Christ day 30:36 structures looked in those elongated mitochondria which represent the more functional pro- survival State what 30:42 about those uh Roto mitochondria the fragmented ones well to me um this is 30:48 going to show in a second the the christe looked more like sad balloon animals they were very swollen um and 30:56 didn't look anything like the ladders that we had seen in those elongated mitochondria and so we were we knew we 31:02 were on to something because nobody had ever really looked at um them in this detail but if you've been paying 31:09 attention you know that we are not satisfied by talking about ladders or 31:14 sad balloon animals we want to transform these words into quantifications and so 31:20 inspired by uh a lot of the work I did as an undergrad my lab dedicated quite a bit of time to figuring out how we could 31:27 transform these models and these uh images of mitochondria into useful 31:32 numbers so we could look for Meaningful differences and we actually borrowed some methods from the computer vision 31:39 community so anyone who drove here on autopilot mode in their Tesla um behind 31:44 you know uh behind this is um data that's used called lar data which represents um the complex geometry of 31:51 three-dimensional objects within uh the environment we used um we were inspired 31:56 by similar thing uh technology to be able to represent our data in a completely new way that opened up the 32:03 possibility for us to quantify it very precisely and so what we did is we used 32:09 this information to represent our membranes as a meshwork of triangles and 32:15 so this is very exciting to me and maybe you now because we love quantifications when I tell you that each one of these 32:22 triangles gives us an opportunity to make a measurement so look at how many 32:27 triangles there are hundreds of thousands of triangles that we can use to to measure and describe how these 32:34 membranes are structured and so we went crazy on this we measured all sorts of things we measured the distance between 32:42 membranes how they're curvature which is a fancy way of saying how sort of like curved or flat they were um as well as 32:50 their orientation and this is my favorite way that we represent our data because to me this is sort of where 32:56 biology meets art meets quantifications what we're doing is we're essentially 33:02 assigning a value so in this case the distance between membranes to a color 33:07 and then each triangle that has a certain value encoded a measurement encoded it we're representing that value 33:13 onto the membrane itself so it's kind of like looking like a topological map of 33:19 the US where you can see all the regions of the mountain chain it's it's a little bit different uh analogy it's certainly 33:24 at a different scale uh but this is a really powerful way to look for local changes in those 33:30 quantifications but of course one of our main goals is to compare across the 33:36 different groups and so what I'm showing here is um some of our data where each of these points represents uh a 33:42 mitochondria that we've measured and we're looking at the distance between that outer and inner membrane and we're 33:48 comparing between the elongated or the functional Pro survival and the Damage proel death and uh what we do in biology 33:56 is we run our stati ICS and then we represent that as asteris here and generally the more asteris you have the 34:02 more differences there are and so what we found is that there were many differences like we were seeing visual 34:08 but now on a quantitative way and in fact we took many different measurements I don't have time to go into all of them 34:15 but what we found is that whether or not we were looking at these Pro survival Linguini mitochondria or the risoto ones 34:22 there were significant but opposing changes at nearly everything we measured and this is important to us because it 34:29 suggests that if we can learn the shapes of these membranes at this detailed level we can understand more about how 34:36 mitochondria are functioning or not functioning in different states and so 34:41 this has really opened up a lot of opportunities for my lab to probe this further to understand what is mediating 34:46 these changes but of course when you're the first to look at something you have an opportunity to see things that nobody 34:52 has ever described before which is exciting and also anxiety producing uh 34:58 and so it's kind of like being an archaeologist going on a dig except for we like to think we're molecular 35:04 archaeologists and one of the things that my grad student who's very talented and very observant found were these Dome 35:10 structures in the mitochondria that we started calling volcanos or rainbows um 35:15 and so this is another really exciting opportunity uh that we have to now try 35:20 to figure out where we we have something we have the ancient Relic but we don't know what it is and so now we're doing 35:26 all of the experiments to try to figure out what it is but we think we're on to something because we we think we see 35:32 although this is very preliminary that uh how these are organized in the mitochondria changes depending on uh 35:39 whether we're looking at these different um Linguini versus risotto 35:44 mitochondria another exciting area that my lab is interested in is really probing what's happening during this 35:50 fion process because as I mentioned it's really important for mitochondria but if it goes hay wire It's associated with 35:57 with uh dysfunction and many diseases and so we were the first to apply this 36:03 Cutting Edge technology to look at mitochondria dividing and uh you can see 36:08 that here this purple is going to this dumbbell shaped structure is going to be the mitochondria and what we're interested in looking at are sort of 36:14 these cables running across it which kind of look like guitar strings to me um these cables are uh as well as these 36:21 blue structures that are kind of sandwiching the cables they're really important for dictating uh where and 36:27 when mitochondria divides they're kind of like the components that exert a little bit of peer pressure on the 36:32 mitochondria to tell it when and where to divide but we don't know how they do this and so by capturing the detailed 36:38 organization of all these components we're trying to build a better picture of how they might be functioning in this 36:46 role uh finally the last thing that we're interested in is trying to think 36:52 about how we might be able to turn the knobs on the system uh and Jamie 36:57 mentioned that my lab is considered one of these basic biologies or fundamental biology Labs but I have to tell you 37:04 being at scripts and being surrounded by all of these drug Discovery Labs rubs off on you a little bit and so I'm very 37:12 fortunate to be able to partner with Labs that are very good at doing this and the lab I'm partnering with is uh 37:18 the lab of Professor Luke wisman and we're trying to figure out if we can reverse or prevent this fragmentation 37:25 because it can be very uh destru destructive and so uh through collaborator we've gained access to um 37:33 cells that were graciously donated to us by patients who have mutations that um 37:38 these mutations lead them to have a mitochondria that are very fragmented and so we were curious if we could 37:44 actually uh identify molecules that would turn these risoto mitochondria into Linguini and so um we identified uh 37:53 two molecules um that look promising to do this of course no one in the audience 37:59 is satisfied just by these images my grad student wasn't either and so she developed a nice approach to be able to 38:04 quantify these um but we really think that this is the beginning of something very exciting now I want to caution we 38:11 are very far far away from any uh sort of idea that these could be used as 38:17 treatments or medicines or Therapeutics really what we're excited about is the potential of using this as a tool to 38:24 understand mitochondria more however the more that use this tool the more that we can help design and understand this 38:31 system to one day potentially lead to new Therapeutics for uh some of these disorders associated with mitochondria 38:39 dysfunction and so I hope today uh what you've taken away from this lecture is 38:45 that mitochondria are not just the PowerHouse of the cell they're actually much cooler 38:51 than that uh they take on lots of different shapes inside of the cell and 38:57 that these shapes uh are more and more we're starting to appreciate important for their function I hope you've also uh 39:04 gained a little bit more of an appreciation like me for the power in using microscopes to really visualize 39:11 the Unseen World and especially an appreciation for how much of life is um 39:17 important beyond what we can see with our with our human eye and similar to 39:22 how life is extends across scales I want to acknowledge all of the support I've 39:28 received across different scales so first I want to acknowledge my incredible team of researchers here both 39:36 uh past and present I just want to say what an honor it is to be part of this 39:42 team you guys are so talented and um I'm trying to be serious while this video is 39:49 going uh but yeah in all seriousness uh you make it a joy to come to work every day and work with you and I couldn't 39:54 have done it without you uh I also want to acknowledge the support of um my friends and family and colleagues some 40:01 of which are in the audience today uh I want to uh acknowledge my three best 40:06 girlfriends who have supported me throughout my journey as well as um my colleagues and in particular my husband 40:13 um Michael who uprooted his life to move 2,000 miles away so I could go after my microscopy dream so thank you so much 40:21 and finally I want to acknowledge the community support I've been very fortunate to receive uh financial 40:27 support from several foundations that really enable me to go after these bold and uh Brave scientific ideas and lastly 40:36 I want to thank all of you both in person here tonight and online thank you 40:42 for taking time out of your busy schedules on November 6 2024 to come 40:48 here and whether you are uh like uh Sheila wisman who have seen every front 40:54 row lecture or you are are this is your first one thank you so much it's been 41:00 such a pleasure to be here and I look forward to the Q&A now more than ever we 41:05 as scientists really need the support of the community and I think this support is two ways and I view my role as a 41:12 scientist and talking to the community is really important to convince you all that what we're doing is important for 41:18 human health and so thank you so much for coming on this journey with me learning about the two very important 41:24 women in my life and how this has transformed uh my view of Science and I also want to say if you're interested in 41:32 uh participating more in this journey there's many ways that you can contribute to the scientific process of 41:39 course the most direct way is through a financial investment but if that's not really in the cards for you I want to 41:45 encourage you to really think about how you can be an advocate for scientific research in your own communities I think 41:53 it's pretty simple because pretty much every medicine that you or someone you love has taken came from a discovery 41:59 like Labs like mine and so talk to your friends neighbors and colleagues about 42:04 uh the cool science you've heard at scripts research and really advocate for policies that will promote uh scientific 42:11 funding and uh and continue coming to these wonderful events we love seeing all your faces and I look forward to 42:18 discussion thank you so much [Music] [Applause] [Music] 42:36 I think we should take you on the road uh great job um so so um so if 42:45 someone has a question L you know put your hand up and we'll get to you with a lightsaber there's someone with that um 42:52 so you know the I'm still thinking about the the fusions and the fishion and then 42:59 you talked about how you know there's an outer membrane and then there's the inner membranes and so if you're 43:05 pinching off you got to pinch two of those things and make sure they don't get confused and then if you're joining 43:11 you have to break both of those open and and so how does it all work yeah yeah 43:17 it's just but yeah so it's it's a lot it's more complicated than just a cell dividing where you get one membrane so 43:23 absolutely so what how does that all get organized yeah I mean this is you've 43:29 touched on a big question that we have uh in the mitochondria biology field and 43:36 I sort of uh touched on it here a little bit in my talk and the reason why we still have the it's kind of seems like a 43:41 fundamental question you know how do you have two barriers that need to divide how do you do that um but really the 43:47 challenge has been is that while we're able to see what can assemble on the mitochondria just before it divides we 43:55 don't have a detailed picture of what's actually happening to those membranes when it divides this is something that 44:00 my lab is really interested in discovering and what we we think is happening is that it depends on the 44:08 context it depends on and I didn't go into this but there are many different Pathways to how this Vision um this 44:16 division can work and so that opens up a whole box of complexities so the short 44:21 unsatisfying answer to your question is we don't know but it leaves a lot we 44:29 yes so maybe the other thing just in general i s found myself wondering about 44:35 you know what's the time scale of it so you s you know you have Linguini you have rotto you have normal and and you 44:42 know so you get up in the morning and you're hungry are are you in Linguini 44:47 land or you know or or what's you know for a normal cell what is the time scale 44:52 under which you would undergo these morphological changes is it like all the time or is it you have to be really 44:59 hungry for a long time before you get this that's a great question uh so it's 45:05 difficult to say about every mitochondria in every cell in in our body um but there is some interesting 45:12 research that suggests that this fusion and fision pro process is connected to 45:17 our circadian rhythm right our light and day cycles what tells us when we should go to sleep at night when it's dark and 45:23 when we should wake up in the morning um for us in our in laboratory setting we 45:28 Al often use model systems and what that means is that we have sort of a simplified version of what might be 45:35 going on inside of our body and oftentimes we use little tricks to help us tip it one way or the other and so we 45:43 have very powerful tricks that we can actually just put a small molecule on and within seconds the mitochondria 45:49 divide and so this is how we're able to kind of push the balance and study these these complex processes um so I think 45:57 there's still a lot more to know about uh what's going on there um but you know 46:02 again gives us lots of areas to cover great I I I see we have a question back here please yes thank you uh you've 46:09 talked about changes in morphology of the mitochondria in sort of healthier 46:15 disease situations but I was wondering about the morphology in different cell types and if you can learn anything 46:22 about how any differences in cell type relate to like energy consumption or you 46:30 know other fake factors that might go into this yeah that's a great question 46:36 um I if I had you know hours with all you I could have gone into even more of 46:42 the complexity you you hit it right on the nail that um there are the the way 46:47 mitochondria is shaped I I prevent I presented a somewhat complex but simplified view of this in that um the 46:55 reality is is that it really does depend on what tissue type you're looking at 47:01 and what's cool about the mitochondria is even though they have all of the mitochondria and in our cells in the 47:07 human body have the same basic makeup the shape can be fine-tuned for its 47:12 function so for example the mitochondria and the Heart they are supercharged to 47:17 be energy producers because that's really important for the heart right um and so their shape and their structure 47:24 is very different from let's say for example examp Le uh the mitochondria that I was showing here which are more 47:30 like reminiscent of mitochondria that might be within the the cells of our skin and so there is a lot to learn um 47:37 about the shape of mitochondria and different tissues and this is something that's important for us as researchers 47:43 to take into account that when we're looking for changes in shape we need to account for that that um what we're 47:49 comparing to is is really Apples to Apples and not apples to oranges or brain to kidney so to speak 47:58 oh we question down front yep that was a fantastic talk thank you really 48:09 wonderful I started off as a physicist and then a biophysicist so my view of a 48:17 cell was a nucleus and one mitochondria and I'm looking at the 48:23 Jillian mitochondria and I'm I'm wondering how does the cell regulate how 48:29 many of those things what density it needs I mean surely there must be I mean 48:36 they can't go while dividing so there must be some way of regulating them it's 48:42 a little outside what you're working on but it just struck me as phenomenal how many 48:51 there are yeah how does the the cell keep track or keep tabs on all of them exactly yeah I mean again this is it's 48:58 it's very complex there's lots of Pathways that not not only control what I talked about today the division or the 49:05 fusion of them which really doesn't change the amount right you're just sort of breaking it up into pieces or putting 49:10 it together like Play-Doh but there are biogenesis or um there are Pathways that 49:16 lead to the creation of mitochondria when necessary um something I think is cool um is that the division of the 49:23 mitochondria is coupled to the division of the cell and when you think of this from like a practical perspective it's 49:30 like the cell wants to put the mitochondria into little pieces because it's easier to partition it's like um 49:37 you know uh I don't know like partitioning things up I don't have a good analogy on the Fly for this 49:43 one but uh yeah it's kind of like breaking something up into little pieces it's easier to make sure you they're 49:48 evenly distributed and I love I love the the beauty of the Elegance of that 49:54 system uh we have a question back 50:01 here hi thanks for the talk um I'm curious about kind of the transfer of 50:08 like healthy versus disease mitochondria between cells you spoke a bit about pharmacological methods to kind of turn 50:15 you know the Linguini into risoto or vice versa um what about like you know 50:22 tunneling nanotubules to take healthy mitochondria and transfer them into to 50:27 you know disease cells yeah this is um an area that uh 50:32 people are looking into this idea of can we repopulate um you know damage 50:38 mitochondria populations with healthy ones uh this is something that my lab isn't doing but it's certainly something 50:44 uh that's in the field and um one thing I'll say about that is actually this can 50:50 is a strategy that some cancer cells can use to actually proliferate um and in 50:55 particular the type of cancer my mom had it's known that those cells are actually 51:01 um taking mitochondria from other cells to really enable them to continue to 51:06 proliferate and divide um so it's kind of like Pirates like hijacking them um 51:11 so this in terms of a therapeutic um I think it's there's challenges as you can 51:17 imagine in in doing this um but it's definitely a strategy um that is people 51:23 are pursuing thank you so so I want to I'll come to you just in one second uh so um 51:31 Danielle and I actually collaborate we do we have a joint joint project and one 51:37 thing I can confirm for the audience is you every once in a while we get to a 51:43 certain point and Daniel just jumps up and starts making lists on the Blackboard so so this part I've seen 51:48 this I've seen this a few times so my question is and you know in in some of the pictures there were just there was 51:55 all these big black dots all over there which are in fact the 52:00 ribosomes yes and and I'm sorry I didn't talk about know know sorry I'm not 52:06 feeling it I'm not feeling so um but it made me think about so there's plenty of 52:12 ribosomes that are on the outside of the mitochondria yep and they're making proteins that go inside the mitochondria 52:20 sure but so I never really thought about it but you're fusing and fishing and you 52:26 have but it's not only ribosome there's all this stuff out there so how you know how do you choose where do you clear the where 52:33 they go just clear the counter and then divide or you know what what is going on 52:38 yeah so uh I can indulge in talk about ribosomes because they're related to the mitochondria um so yeah there this uh 52:46 what's interesting about the mitochondria is that Jamie mentioned this I didn't talk about it at all but 52:51 they're unique in that they contain their own small genome or DNA so this is separate DNA from that that we think 52:58 about is in the nucleus and this is um sort of an an ancestral relic of how we 53:05 think mitochondria came to be which is that there was a bacteria that engulfed another bacteria and then retained some 53:11 of that DNA but what's interesting is even though they have their own DNA it only encodes for 13 proteins and there 53:18 are over 1500 proteins that make the mitochondria function so there's clearly 53:24 a lot of cross commmunication protein have to come in they go out the ribosomes there's a small set of 53:30 proteins where the ribosomes actually dock directly on the membrane itself this is a very rare and Elusive process 53:37 that my lab is working on we have a a paper and review right now looking at the structure of these um but something 53:44 else that's interesting is mitochondria have their own ribosomes um and so whether this idea of U ribosomes on the 53:51 outside coordinating with ribosomes on the inside is something um that people haven't been able to really test before 53:57 and something that we're interested in looking in okay here endeth the ribosome discussion thank you I appreciate I 54:03 appreciate it down here question great talk Daniel thank you uh I'm curious uh 54:09 you talk about healthy cells and cell death the question is uh does 54:17 the disintegrating mitochondria cause cell death or is it a 54:24 symptom of cell death yeah that's a great question so mitochondria are a 54:30 really important part of um what we call the cell death pathway or apoptosis and there's a molecule that's 54:38 actually normally kept um tightly within the mitochondria within those cristate 54:44 called cytochrome C and it's only through a series of very regulated events that that molecule gets released 54:51 into the cell and there's a reason why it's so regulated is because once that molecule is released it really triggers 54:57 this cell death pathway so you don't want that to happen willy-nilly to any any cell types um but there are indirect 55:05 so that's a direct way that mitochondria contributes to to cell death but there are indirect ways right if if the 55:11 mitochondria aren't able to produce enough energy for the cell this is going to mean that there's a lot of Downstream 55:17 effects um where there's not enough energy there's not enough proteins being made they're not functional and so 55:22 that's sort of like an indirect way that the dysfunction of mitochondria May contribute to triggering the cell death 55:29 pathway um although it may not happen through the mitochondria itself okay one one more about 55:37 here hello great talk um I was curious the mitochondria can reside in 55:45 multiple position within one cell let's say for example a projection neuron can 55:51 be very lengthy and in that case do you think mitochondria status is 55:57 synchronized across the cell or it is more like a local 56:02 manipulation yeah that's I think your question is getting at when you're kind of when you have these specialized cell 56:08 types that have very long projections how what is is there 56:13 something unique about those mitochondria and I think um we we believe that there is something unique 56:20 about the mitochondria that are close within near the nucleus of the cell which is a lot of the mitochondria 56:26 showed today versus those that are farther out in the projections and they might actually have different roles 56:31 whereas some of them might be more involved in producing energy locally in those distal locations maybe the ones in 56:37 the nucleus are performing other functions and so yeah and certainly there are differences and actually we 56:43 have a really nice collaboration with um a lab here in the Neuroscience Department really trying to look at how 56:49 the structure of uh mitochondria changes whether we're exciting or inhibiting a 56:54 neuron and so um stay tuned tuned for for more on that all right I think I 56:59 think we should we're at the hour um I just maybe ask you one last kind of just sort of you know future forward-looking 57:06 statement you know what so you you brought this this cryo and the Fib 57:12 milling and all of that to to scripts and that so Cutting Edge puts you in the position to ask questions that other 57:18 people can't but you know so what's the next great thing where where are we 57:23 going in structural biology and and you know so what is if I had a checkbook 57:30 what would be the gadget that I could buy you that you know that would where well 57:37 I got a list so I only can choose one okay it's it's always good to have a list well okay so um the The Cutting 57:44 Edge technology when I started my lab was our I showed it in that animation where we're micro Machining individual 57:50 cells and we're doing this to expose regions but of course the dream is to be 57:56 able to do this on more complex systems like tissue right um we could look for 58:02 example at an entire zebra fish uh or an entire uh small worm that is often used 58:10 in research and it becomes more complex as you have something that's a little bit bigger um to do this for technical 58:17 reasons but there are Technologies out there now that would enable us to look at that and the reason why that matters 58:23 is because that would represent more the state the physiological state right 58:29 ultimately when we're removing neurons or cells from a body we try our best to 58:35 recapitulate what it's like when they're inside of our body but there are caveats to that so being able to do it within 58:41 its native environment is really I think the holy grail and so that's that's the item I would put on my wish list coming 58:48 right up coming right up so um all right well look thanks so I hope you'll agree that the the future of scripts is secure 58:56 uh we're really uh proud to have you here as a faculty member um and unfortunately this is our last front row 59:02 for the year we'll take a break stay tuned there will be another calendar year but I think we're scheduling and 59:09 the next one will be in February so thank you all have a great holiday 59:15 period and welcome back to the front row