Jared Rutter (U. Utah, HHMI) 2: Mitochondrial Metabolism and Cell Decisions
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- เผยแพร่เมื่อ 6 ม.ค. 2020
- www.ibiology.org/cell-biology...
Dr. Jared Rutter shares new insights into the interplay between mitochondria, metabolism, and cellular behavior.
Mitochondria are integral to the metabolism of eukaryotic cells, yet many of their properties are not fully understood. In Part 1 of this iBioSeminar, Dr. Jared Rutter lays out the foundational knowledge of mitochondrial structure and origin, and shares what is currently known about mitochondrial roles in metabolism, protein homeostasis, and signaling. He ends by highlighting a focus of his research group: to unravel the functions of uncharacterized mitochondrial proteins.
In Part 2 of his talk, Rutter describes his group’s work to unravel the relationship between the activity of the Mitochondrial Pyruvate Carrier (MPC) and the behavior of numerous cell types, including cancer and stem cells. His group found that forced expression of the MPC in multiple stem cell models led to reduced “stemness” and proliferative capacity, and that MPC inhibition could promote organoid formation in culture and tumor formation in vivo. These data indicate an important link between mitochondria, metabolism, and cell behavior.
In his Part 3, Rutter emphasizes the challenge of mitochondrial protein synthesis. How do the components of the electron transport chain (ETC) assemble in the right stoichiometry at the right time? Rutter introduces the LYR family of proteins, which aid assembly of ETC components. LYR proteins interact with a common binding partner, the acyl carrier protein (ACP), via a unique fatty acyl moiety on ACP. Rutter’s group showed that ACP acylation is necessary for assembly of the ETC and activation of oxidative phosphorylation.
Speaker Biography:
Jared Rutter is a Professor of Biochemistry and holds the Dee Glen and Ida Smith Endowed Chair for Cancer Research at the University of Utah. Dr. Rutter received his PhD from the University of Texas Southwestern Medical Center in 2001, working with Dr. Steve McKnight. After receiving his PhD, he spent 18 months as the Sara and Frank McKnight Independent Fellow of Biochemistry before joining the faculty at the University of Utah. As of September 2015, Dr. Rutter is an Investigator of the Howard Hughes Medical Institute. In addition to leading his laboratory at the University of Utah, Dr. Rutter is also actively involved in translating these academic discoveries into therapies as a founder, consultant and board member of several companies and venture firms. Dr. Rutter also serves as co-Director of the Diabetes and Metabolism Center at the University of Utah and co-Leader of the Nuclear Control of Cell Growth and Differentiation at Huntsman Cancer Institute.
rutter.biochem.utah.edu - วิทยาศาสตร์และเทคโนโลยี
Thank everyone, all the people working on this channel and all the professors for spending their time to produce these lectures for the general public.
Thank you Professor Rutter for letting us know more about the functions of mitochondria.
Yesterday evening, I embarked on this journey of learning about DNA, RNA, mitosis, cell structure, history of microbiology and now I‘m learning about Mitrochondrial functions. The internet is an insane place. 😂
Can you provide links of your journey of learning? It appears an interesting trip of learning to follow if you don’t mind.
I love this channel sooooo much ♥ A lot of beautiful knowledge.
Thank you so much.
Glad you enjoy it!
Fascinating topic excellently explained. Thank you very much for sharing!
Great capacity to make understandable the complexity of mitochondria
fantastic works! Great talks!
Excellent presentation, very helpful
Awesome brain storming about how we can target pyruvate metabolism in drug discovery context!
where can I get a poster with that picture of the mitochondria on the opening slide? what a beautiful visual
I wonder if mct4 is inhibited thus reverse lactate and pushes Pyruvate down if this process then downgrades mtor?
How does this pathway change in ketosis using ketones instead of glucose?
Does fasting thus mitophagy allow for better function of MPC or is the lack of two proteins needed constant?
Can we measure mct4? To assume more cell growth ie cancer?
So can you deliver VB 253 via an inhaler, to get a more selective effect? Targeted specifically at the lung tissue?
Does MPC has something to related with BCL2 protein and apoptosi signal?
From another video perhaps on iBiology, but certainly on TH-cam I learned that mitochondria synthesize proteins used to maintain the orderly structure of DNA in the nucleus. Could it be that the inordinate high number of mitochondria in stem cells serves either as a high volume protein factory or as an error correcting mitochondria production base?
I didn't got the relationship b/w stemness of the cell and MPC
In this case, can MCT4 or MPC be potential/alternative solution to slow down the chronological process of pulmonary fibrosis? ( Some Coronavirus infected persons may develop long term pulmonary fibrosis.)
Thank you
So do we know what the key to turning autophagy on and off is?
Amazing!
A video of MPC using PyMol would be nice.
I would really like to know if there can be changes to diet that may promote the same positive effects you hope to find in a drug. I realize there is little financial benefit in teaching prevention but I hope research will support this.
Right around 23:45, it was suggested that maybe better treatment drugs could be developed. What about the nutrition side? What could be done for prevention in the first place for the growing community of health focused sector?
So, what is the status of VB253 now? Human trials?
why don't you consider ketone body to acetyl coa powering the intestinal stem cells mitochondria?
Forgive me if this sounds stupid, but I'm new to biology.
If increased lactate concentration in the cytosol leads to greater influx of pyruvate into the mitochondria, which in turn ups the expression of MPC, which seems to have the effect of reduced oncogenesis, then would it be reasonable to deduce that high-intensity exercise (feeling the burn) could reduce the likelihood of cancer?
Or am i barking up the wrong tree?
By inhibiting the lactate transporter MCT4, lactic acid accumulates in the cytoplasm and not in the extracellular environment; Accumulation of lactate in the cytoplasm results in an upward expression of the mitochondrial pyruvate transporter in the mitochondrion (PMC1 / PMC2), which suppresses stemness and causes the cancer cell to differentiate.
Do we know that low expression of MPC is CAUSAL to cancer behaviors of the cell or a CONSEQUENCE of something else?
yup. the paper cited in this video (Schell et al) discusses the controls used in their experiments.
Wednesday January 4, 2023. Mitochondrial Metabolism and Cell Decisions; (Otherwise) Metabolism Regulation in the Context of Cell Differentiation Via Mitochondrial DNA and/or Mitochondrially-Expressed Proteins (Nuclear Gene Expression Vastly Predominates). It would be surprising to Me either way to have Mitochondrial DNA relevant or even causative Of Oncogenesis because Metabolism Program is simply included in so many Transcription Factor (TF) irrespective of Tumor Suppression or Proto-oncogenic Mechanism therein. I have theorized the selective suffocation and/or Asphyxiation of the Neoplasms via Some Mitochondrial Specific Receptor/Channel just as Cyanide Poisoning is active in the Mitochondrial tissue, namely Cytochrome C Oxidase Mitochondrial Protein (Enzyme). Mitochondrial Enzyme Inhibition could be a Proof of Concept but the Selectivity and Exclusive Selectivity is the Main Conundrum which is certainly made easier by Monoclonal Antibodies which are essentially the most programmable Agents of Biological Significance otherwise just about any non-Biochemical Affinity is Reasonably Foreseeable. Anyway, the PMC Inhibition and Proteomics therein is a fabulous exercise of a Pharmacological and Recombinant Technology Mechanism Possibility...Ph.D Rutter et al, Es geht gut zu Gusundheit machen aber besser soll die Wissenschaft des Lebens als Weiss/Schwarz Wissenschaft sein. Menschheit Und die Verbesserung Da ist ein Grosse Ende aber Grosser sind die unbekannten Moeglichkeiten. Heil!
Love One Another
Highly complex, sophisticated engineerical systems... and definitely designed by someone.
no, not by someone, it is the result of of millions of years of evolutions of systems, of trails and errors that lead to cells that can sustain themselves sufficiently to adapt to their environment and compete for thriving
@@Fossilized-cryptid Wrong! irreversible complexity. The motors don't just fall together over millions of years. They came pre-assembled, and already working.
@@bigcountry5520 ok
Wow, I didn’t know Ryan Reynolds was so smart
elude elude elude
allude, allude, allude ! ;-)
Fascinating! But consider evolution: 3:25 _"There's an MPC1 protein and an MPC2 protein. Those two proteins come together. Both of them are _*_absolutely required_*_ for the function of this complex. And in the absence of one or the other, the other one just gets degraded."_
Which one of these proteins originally evolved first? And wouldn't the tenets of natural selection be _violated_ when that organism selected and preserved that useless first protein for eons of generations before the second one evolved?
Possibly one was originally synthesized by the mitochrondria, but later migrated into cellular DNA as mitochrondria lost the ability?
That wouldn't solve the problem with natural selection, @@DustWolphy.
@@KenJackson_US perhaps if the proteins evolved to function as a means of coordination between the cell and the mitochondria. There is no saying they don't also have other functions within the cell.
Proteins are highly specific, @@DustWolphy. Their function is highly dependent on their shape, which is totally determined by the sequence of amino acids they're made from. Just a few changes (mutations) and it no longer even folds correctly, much less functions as anything. It just makes no sense for natural selection to select and preserve a non-functional protein.
@@KenJackson_US "modern" proteins are 'highly specific' doesn't necessitate their ancestors were. Without knowing exact details of these proteins and their all kind different close relatives in other organisms (mitochondrias of various species and ancestral 'free' bacterial relatives (assuming here that there are a big family of such protein pairs that are "highly dependant" from each other for functionality of the MPC as a whole in corresponding organisms) it's still easy to think possible ways how such protein pair may have evolved.
For sake of simplicity, I assume some form of protein synthesis has evolved and exists already
1. Low efficient "proto-MPC" protein is 'invented' by natural selection, capable to attach to inner membrane (probably at the stage of sort of proto-membrane, different from its current structure and composition) and help molecules to get through the membrane. Minimal efficiency surplus is enough to make differences in the organism's fitness due critical nature of the function, thus the novelty rabidly spread across the population.
2. Some other molecule/protein appears similar way (via mutation for example) that help catalyse the function of proto-MPC to be more efficient in its task. That molecule doesn't even have to be protein at the first phases of the evolution of modern MPC2, as "original" catalysing molecule could get replaces by functionally similar protein if/when such molecule emerges.
3. Better and better efficient catalysts appear and co-evolve with better and better versions of 'proto-MPCs', that become more and more efficient together, but also more and more mutually dependant from each others to perform the task properly. Note that there might even have been more than two molecules/proteins taking a part to the functionality of Proto-MPC that are now reduced out entirely from the structure and functionality of the modern MPC1-MPC2 protein pair.
4. Minor efficiency improvements accumulated gradually by natural selection. Past 0.5% efficiency compared to current efficiency is better than previous, past 0.01% efficiency.
5. Modern MPC1-MPC2 pair maybe incredibly specific and efficient complex compared to the past iterations of the structure of functionally homological, ancestral molecular complex, but that doesn't anyway imply it would be "perfect" in its current form and in what it does, nor that there couldn't be potentiality for further evolution and improvements of that same function.
Other option is then to assume some sort of "designer", which directly imply that:
1. Assumed designer must be at least as complex than everything it allegedly designed.
2. For such "designer" to appear to design anything, some kind of darwinian process of natural selection must be assumed, as if not,
3. then we must also presume that something "designed" "the designer", which leads directly to next level "design", which leads to the next, and, next ad infinitum... and thus, to
4. Infinite regression, that is both dramatically less probably scenario, but also doesn't answer the question we are asking in the first place.
Thanks for the great work and the presentations. I hope your therapeutic venture is successful. A friendly suggestion--stop using the word, allude! You are using it incorrectly, and too often! Degrades the appearance of competence that your work deserves.
23:30 How do the cells know what metabolites they have? They have a brain and consciousness, and each organelle has a brain.
If they were conscious they would party all the time
no
How many mice are degraded to genetic-fodder - besides those utubers that terminate mice for fun
Not enough.