How Mitochondria Control Your Metabolism | Dr. Jared Rutter
In a Nutshell
Mitochondria act as metabolic decision-makers by controlling pyruvate's fate: burning it for ATP or converting it to biomass via lactate. The mitochondrial pyruvate carrier (MPC) is the critical gatekeeper for this allocation. When cells prioritize biomass over energy production—whether in cancer, failing hearts, or aging—they lose their specialized function and contribute to disease.
These notes were generated by AI and may contain inaccuracies.
There's a widely accepted hypothesis that mitochondria with excess energy leads to problems. Many people have heard of reactive oxygen species, which are forms of oxygen that become reactive and end up damaging proteins and nucleic acids. One contributor is mitochondria that have too much energy. The form energy takes when extracted from food before conversion to ATP is powering the mitochondria. When mitochondria are overpowered, this leads to a state susceptible to generation of reactive species that damage the genome, create mutations, damage proteins, and create many problems.
When thinking about metabolism, the body's metabolic rate represents calories in, calories out. The body's metabolism is the sum total of what is ingested through eating, drinking, and breathing that enters the body and gets processed. The results are individual molecules like amino acids and sugars that distribute throughout the body, go into individual cells, and enter cellular metabolism. Cellular metabolism can be thought of as a map with an entry point. A molecule of glucose comes into a cell and can be chemically modified in various ways to fulfill the needs of that cell. The cell processes molecules to fulfill particular functions, leading to release of waste products eliminated from the body.
The metabolism of the body is the sum total of the metabolism of each one of the 30 trillion cells. The passions lie in understanding how individual cells choose to take up certain nutrients, how they process them, turn them into other things, how they use them to fulfill particular functions, and how this is regulated. The coordination of each cell working together allows complex activities, and this happens at the level of individual cells.
There's a partial answer to why young cells produce more energy than older cells. Mitochondria become less energized and less effective as we age. The reasons are partially clear but largely unclear. There's accumulation of damage from the orchestration of metabolism throughout the body, which is expensive not only in terms of food needed to fuel it, but in terms of damage that comes as a side effect. The accumulation of damage over time correlates strongly with aging. There's evidence in animal models suggesting accumulation of damage is a big part of the aging process.
Aging is fundamentally a cellular phenomenon. The processes that lead to aging are the accumulation of processes that happen at the level of individual cells. We're at the precipice of understanding this because of tools starting to become available that will help better understand cause and effect and specific molecular features of the aging process.
Mitochondria are believed to have been the result of an endosymbiotic event where a free-living bacterium was engulfed by another cell and domesticated. The main genome of the cell is DNA contained typically in the nucleus. Mitochondria have their own separate genome that is a relic of the bacterium they descended from. This genome is in a circle like bacterial genomes, whereas the nuclear genome of eukaryotic cells has linear chromosomes. That genome performs essential functions and codes important proteins that enable mitochondria to function as the powerhouse of the cell to extract usable energy from food.
Mitochondria are completely inherited from the mother through the egg. When sperm fertilizes the egg, the genome from the sperm gets into the egg, but the cytoplasm of the sperm does not. The mitochondrial genome comes completely from the mother. This has implications for inheritance of diseases that are mitochondrial in origin.
Mitochondria can be found throughout cells regardless of cell shape. Neurons have one-meter-long projections where mitochondria transit from the cell body down those projections. These mitochondria play essential roles at nerve terminals by generating usable energy for neurotransmission. The extraction of energy and turning it into usable form, typically ATP, is a key function of mitochondria. ATP is needed in virtually every place of every cell, and local production makes it more efficient.
When a cell is crawling, like an immune cell chasing something, mitochondria distribute toward the leading edge. Crawling is energetically expensive and requires a lot of ATP. Mitochondria congregate at that leading edge where ATP is being consumed.
Virtually every cell has slightly different mitochondria suited to the demands of that cell. A cardiomyocyte has one job: to contract every second of every minute of every hour of every day. Its mitochondria are wired to consume whatever is available and make ATP because that ATP is crucial for cell contraction and heart beating. Cardiomyocytes have very little turnover.
Stem cells lining the intestine enable gut lining turnover every 5 to 7 days. ATP is not the major demand of these cells. They need to completely duplicate themselves constantly. Their metabolic program is very different from cardiomyocytes. They need to replicate all DNA, duplicate all proteins, duplicate all membranes and lipids rapidly. The mitochondrial wiring enables production of biomass required to make new cells, which is completely different from cardiomyocyte mitochondria.
Every cell has a particular purpose and function for the body, and mitochondrial demands differ depending on unique functions and demands of that cell. In one cell, there can be two different kinds of mitochondria with two different functions. One tends to be more biosynthetic, producing biomass.
Mitochondria can be adapted for different cellular needs. One type tends to be more biosynthetic, producing biomass, while another is more energy-extracting and focused on ATP production. This represents an overly simplified but generally accurate way of thinking about mitochondrial function and emphasizes the unique adaptability of mitochondria to meet specific cellular requirements.
When food is eaten, it gets absorbed and glucose circulates in the bloodstream, with stored energy available in the form of glycogen. The question arises whether every cell is trying to get as much energy as possible to produce ATP, or whether there's some communication and more democratic allocation of energy. Under non-stressful conditions, the vasculature distributes glucose evenly, or there may be prioritization of organs like the brain, heart, and those involved in breathing.
When food is consumed, the digestive system extracts sugars, amino acids, and fats, triggering signals including GLP-1 and insulin. These hormones are secreted and travel to cells throughout the body, signaling that food has been consumed. Different cells respond differently to these signals. Some cells don't pay attention and continue their normal function, while others care greatly about the information.
Adipocytes (fat cells) respond significantly to insulin by turning on a protein that causes glucose to be taken up into the fat cell. This glucose is converted through chemical reactions into a fat molecule and stored away safely for potentially very long periods. This represents a beautiful coordination mechanism where the organism stores energy when its energy status is good, creating reserves that can be used during prolonged fasting periods.
Insulin has different effects on muscle and other cells throughout the body. The response of different cells to the fed state varies depending on the needs and functions of each cell. Some cells don't care at all and continue their normal business, while others completely rewire their function depending on the metabolic state (fed versus fasted) of the organism.
Insulin is not just a shuttle mechanism but carries information about the size of the signal, which indicates what is likely to be present. This has implications for how cells prepare themselves for different functions. Brain cells can prepare to fire action potentials, while fat cells prepare to store energy. Photoreceptors in the eye continue firing whether eyes are open or closed. Mitochondria drive the ATP production across all these different cellular functions.
Glucose is the dominant carbohydrate that most cells consume. When glucose enters a cell, it goes through a series of chemical reactions called glycolysis. The endpoint of glycolysis is pyruvate, which represents a decision point for the cell. Pyruvate can either be taken into mitochondria and oxidized (burned) with oxygen to extract all available energy, or used differently depending on cellular needs.
Pyruvate is an intermediate, a midpoint from glucose. Glucose is a six-carbon molecule that gets chemically modified down to pyruvate, which serves as a pivot point in glucose metabolism. The fascination with pyruvate comes from the bifurcation that happens at this point - pyruvate can be taken into mitochondria and burned for effective ATP generation, or used for other purposes.
Food can either be converted to energy or to biomass. Cardiomyocytes take everything they can from circulation, burn it to make ATP, and keep the heart pumping. In contrast, intestinal stem cells that repopulate the gut lining every week don't burn pyruvate but instead turn it and other glycolysis intermediates into biomass to enable cell duplication. This represents a critical resource allocation decision that every cell makes constantly.
Activated B cells of the immune system need to make antibodies, which are proteins requiring amino acids. This requires significant resource allocation toward biomass production. The distinction at the pyruvate point represents a fascinating pivot in metabolism where cells organize to make the right resource allocation decisions every second of every day.
FDG PET imaging uses a labeled form of glucose (fluorodeoxyglucose) to visualize cells taking up large amounts of glucose. Tumors take up a lot of glucose, making FDG PET effective for cancer diagnosis. Cancer cells make resource allocation decisions that prioritize building more cells, which is why tumors form - a cell decides to duplicate itself repeatedly instead of performing its normal function.
Viruses have the goal of propagation - making more of themselves to infect other organisms. This represents evolutionary pressure where mutations that improve infection and propagation capabilities get selected. Cancer is fundamentally different because it rarely transmits from one organism to another. The evolutionary scope of cancer is limited to the individual organism, whereas viruses evolve to spread between organisms.
Cancer cells undergo evolution through acquisition of mutations that enable faster division, evasion of immune system limits, and survival despite DNA damage. This represents a continuous process of cancer development where cells become better able to duplicate themselves and evade problems. While the evolutionary process underlying cancer follows the same principles as viral evolution, the motivations differ because cancer isn't fueled by the drive to get from one organism to another.
Bacteria living in the gut and on the skin are driven by the same evolutionary pressures as humans and viruses. They attempt to propagate themselves and fill their ecological niche more effectively than competing neighbors. Their genomes get passed on when they succeed at this. The implications of the microbiome have only been experimentally dealt with in a serious way in the recent decade, though the phenomenon has been known for a long time.
MPC stands for mitochondrial pyruvate carrier. This is a carrier that enables pyruvate to get into the mitochondria, providing a specific hole in the membrane so pyruvate can be burned by mitochondria to extract energy and make ATP. The acronym was named before the researchers worked on it.
It has been known for 60-70 years that mitochondria must have a carrier to enable pyruvate to get in, but the protein was not identified until the late 2000s.
The motivating realization was that many proteins making up mitochondria have unknown functions, despite the organelle being considered the powerhouse of the cell. This suggested mysteries remained that needed answers. The approach was to take proteins known to be in mitochondria but with unknown functions and determine what they do.
MPC1 and MPC2 turned out to be two such proteins. These proteins are found in every cell that has mitochondria, from yeast to plants to animals, suggesting they are fundamentally important.
Twenty years ago, researchers could not say with confidence that all proteins in a heart cell were known. Now they can say with much greater confidence that essentially everything is known about the proteins encoded by the human genome. However, knowing what all these proteins do remains the frontier for the next generation of scientists.
The old way of finding proteins involved grinding up cells, running them through columns with filters that separate by size, and testing different fractions for functional activity.
The discovery involved collaboration between Jared Rutter's laboratory using yeast as a model system and human cells, and Carl Thummel’s laboratory using fly genetics. Data from these different systems triangulated to suggest that MPC1 and MPC2 were the mitochondrial pyruvate carrier. This was validated many times over.
Jean-Claude Martin and his laboratory in Geneva published a paper at the same time showing the same discovery.
The MPC represents the first step toward one destination of pyruvate. Once pyruvate is pulled into the mitochondria, it will be used for something in the mitochondria instead of being used for something else in the cytosol. This has implications for resource allocation decisions that cells make.
Cardiomyocytes want to make ATP to allow the heart to continue contracting, so they need to extract every bit of energy they can. They use the MPC extensively. The question is how they ensure they make just enough ATP to maintain themselves without burning up the structural components.
Cells are not programmed with a spigot and diverter valve allocating specific percentages. Instead, cells measure their resources constantly. Every cell knows how much usable energy (ATP) they have at all times. When ATP gets low, they initiate responses including turning off processes that use ATP and pulling glucose out of circulation to make more ATP.
Insulin tells the body that food has been eaten and to squirrel away energy in the form of glucose. Glucagon is the fasting hormone that does the opposite—it tells fat cells to release stored fat. This released fat can go to other cells in the body, including the heart, which is very good at consuming fatty acids.
Under fasted conditions, 70-80% of energy extraction in cardiomyocytes comes from fat. Even in fed conditions, fat is available for the heart to use. The heart is an omnivore that will burn fats, glucose, lactate, ketones, and amino acids to make ATP.
Neurons are particularly fond of consuming glucose and have limited ability to consume fatty acids. The brain requires some amount of glucose to keep functioning. Glucose is fascinating because diabetes is defined as high blood sugar, which is damaging over years, but if glucose is too low, death occurs within minutes due to brain requirements.
Mice lacking MPC globally do not survive to birth—they die around 12-13 days of development. However, organ-specific deletions can be made using technology developed by Mario Capecchi, who won a Nobel Prize for developing knockout mice.
When MPC is eliminated specifically in the heart, the animals live for weeks but eventually die of heart failure. The hearts become massively enlarged. The animals do not die from inability to make ATP because they can burn fats instead. Rather, they make a resource allocation decision where instead of using glucose to burn it and make ATP, they start making biomass. When cardiomyocytes grow, this creates structural problems for the heart, leading to dilated cardiomyopathy.
The allocation decision in these mutant mice and in people with cardiac conditions is that cells devote too much energy to making more of themselves (biomass) and not enough to doing what they are supposed to do. This decision between making biomass versus using energy to maintain cellular function appears to be a critical balance.
The same principle appears to apply at higher levels—larger animals within a given species tend to live shorter lives than smaller varieties, and athletes in sports requiring larger body mass appear to have reduced longevity compared to those in sports requiring less mass.
Cell identity is a fundamentally important phenomenon that has been understood in some cell types, but questions remain about the extent to which disease is associated with loss of that cell identity. Cell identity is a squishy parameter to measure because there is no function to directly observe what a cell thinks it is.
By the time people reach their 50s, every cell is a mosaic of the original genetic makeup plus accumulated mutations. This represents one form of cell identity, creating a patchwork of former self and newer self within an organ and within a cell type.
Within cell populations, there exists a choice between making more of oneself versus simply being oneself. This creates a conceptually sticky notion of size versus use. The resource allocation decision involves allocating resources to energy versus making more stuff, which could mean another cell or a bigger cell.
There are many examples where making more stuff instead of making more energy is pathological. These include cancer, the heart getting pathologically bigger, and immune cells becoming hyperactivated leading to inflammatory diseases.
Relics of historical and philosophical ways ancestors thought about the world can be found reflected in scientific discoveries made today.
Money functions as a tool that can be exchanged for something. Malevolent behavior in human interactions typically occurs when someone perceives that energy has been stolen from them, usually in the form of time or physical energy. Time is physical energy. Benevolent acts generally involve either an even exchange or a net positive exchange of energy.
No cell can afford to cheat itself if it wants what is best for itself, the organ it resides in, and the organism as a whole. If too many cells cheat themselves, this results in a big heart that doesn't pump effectively.
The discovery of the mitochondrial pyruvate carrier (MPC) came from genetics. Carl's lab made flies that lacked the MPC. The flies were alive but had specific manifestations that could be analyzed using chemistry. Studies were conducted in yeast cells, human cells, and fruit flies by analyzing the results of losing these genes.
By analyzing cells using sophisticated chemical tools, researchers could see that the metabolic pathway from glucose to pyruvate to pyruvate in the mitochondria to ATP was being blocked specifically at the level of pyruvate. This gave the initial hypothesis that these proteins might be the mitochondrial pyruvate carrier, which was then validated in multiple experiments and confirmed by many other researchers over the subsequent decade.
The paper was published in 2012, with the research likely occurring from 2008 or 2009 to 2012.
Yeast has a very quick turnover time, making it useful for experiments. Fruit flies have short generation times, allowing many experiments to be conducted quickly. Fruit flies have many of the same structures that humans have, though not exactly the same. The discovery could not have been made with any single type of organism. The yeast data alone, fly data alone, or human cell data alone would not have been sufficient. Combining multiple model systems allowed triangulation of findings across organisms.
Pyruvate has two major fates: it can go into the mitochondria or be converted to lactate and exported. The decision to burn pyruvate or make lactate is one of the most important metabolic decisions that cells make constantly.
Production of lactate enables ongoing production of biomass. When pyruvate is burned, it turns into carbon dioxide that is breathed out and eliminated. When pyruvate is not burned, the material can contribute to protein production, carbohydrate production, or fatty acids that can be used to make new cells. Lactate mediates this building decision.
Lactate has historically been thought of as a waste product when cells cannot burn pyruvate due to lack of oxygen. When oxygen is not available, pyruvate cannot be burned and must be converted to lactate. This is why during exercise when muscle becomes hypoxic, lactate is produced and causes the burn sensation.
Recent experiments have demonstrated that lactate is an important fuel on its own. The heart is particularly good at consuming lactate and burning it. The heart consumes a variety of fuels including lipids, glucose, and lactate, allowing it to continue beating regardless of metabolic status.
Lactate serves as a shuttle in the context of exercise and brain function. Intense aerobic exercise generates enough lactate that it appears to signal the brain to produce brain-derived neurotrophic factor (BDNF), which builds more neural connections.
Labeling something conceptually can shut down lines of discovery. The moment a label is applied, it often turns out that the labeled item is more important than initially thought. Mitochondria are very good at being a powerhouse and making ATP, but they do much more than that.
There is prioritization of energy sources. Fatty acids are among the most important things to burn first because when fatty acids are in excess, they can be toxic in an acute way. Glucose is toxic in excess but chronically less dangerous than high free fatty acids. Most cells burn fatty acids first when they have them available, likely as an evolutionary response to the immediate danger fatty acids pose.
Lactate has important effects on cell chemistry. If lactate gets too high in the body, it can cause lactic acidosis, which can be lethal. Dealing with excess lactate is important.
Mutations that afford more life and are adaptive are the reason humans exist. The X-Men concept of beneficial mutations aligns with biological reality.
The Warburg effect was named after Otto Warburg, a German scientist in the 1920s who observed that cancer cells consumed less oxygen than expected. Warburg thought this indicated broken mitochondria were the cause of cancer. The thinking from the 1920s persisted for many years.
Mitochondria in cancer cells are not broken. Cancer cells are very good at making stuff rather than making ATP. The oxygen consumption observed in the Warburg effect is a surrogate for the resource allocation decision. Cancer cells use their resources to duplicate themselves rather than burn fuel.
Cancer therapy faces fundamental challenges because cancer cells are our own cells. Unlike bacteria, cancer cells lack antigens that the immune system recognizes as nonself. The challenge is to kill cancer cells without killing the rest of our cells. Many features of cancer cells are not completely new but represent functions that normal cells have, such as becoming more like stem cells.
Cancer cells within a tumor are under evolutionary pressure. Even if a drug kills 99.9% of tumor cells, the remaining 0.1% that acquire resistance through mutation or adaptation can repopulate and make a new tumor that is resistant to the original drug. This explains why tumors can return after initially successful treatment.
Current cancer therapies face the same fundamental problem as single-drug treatments for HIV, where resistance develops rapidly. The solution lies in triple combination therapy, where three drugs simultaneously target the virus or cancer cells, making it extremely difficult for resistance to develop against all three at once. This approach represents the future of cancer therapy, requiring many safe and effective drugs that target different biochemical features of cancer cells.
Oncologists will eventually be able to analyze the unique biochemistry of individual tumors and prescribe specific drug combinations that work together to kill the tumor while preventing resistance development. This could approximate a cure by making simultaneous resistance to multiple drugs nearly impossible.
Recent exciting developments include drugs targeting specific oncogenic mutations, such as KRAS mutations, that work in completely specific ways. These drugs affect only the mutated proteins contributing to cancer without impacting normal cells. However, resistance still develops over time, making combination approaches essential for sustained effectiveness.
David Fajgenbaum, a physician at University of Pennsylvania who cured his own Castleman's disease using combinations of already approved drugs while on his deathbed, now runs a nonprofit called Every Cure. This organization uses AI, cell assays, and tumor biopsies to test approved drugs against specific cancers. In cases where no other hope exists, this approach has successfully cured some patients and extended life in many others.
One notable finding is that using lidocaine during breast cancer surgery significantly reduces recurrence rates, suggesting the local anesthetic has effects on the tumor microenvironment beyond its intended purpose.
Current cancer classification systems based on tissue location (breast cancer, liver cancer, colon cancer) are inadequate because some breast cancers are more similar to certain liver cancers than to other breast cancers. The historical classification system was defined by surgeons who removed tumors, not by the underlying biology.
The specific mutations that cause cancer, enable immune evasion, promote propagation, and prevent cell death are unique to each individual tumor. Understanding the mutational landscape of each cancer provides the ability to select effective drug combinations for that specific tumor.
Beyond genetic mutations, cancer classification should consider the unique metabolism that enables cancer cells to execute their instructions. A cell can have all the genetic instructions to make a new cell, but without the building blocks - the "lumber, bricks, and mortar" - it cannot actually create new cells.
The field has seen increased focus over the past 10-15 years on blocking cancer cells' resource allocation toward building new cells. However, resistance develops relatively easily as cancer cells can mutate and rewire their metabolism to achieve the same outcome through different pathways.
Advanced metabolic imaging could involve drinking a safe fluid, entering an imaging tube at ages 5 and 50, and receiving detailed pictures showing the proportion of metabolism occurring in different organs with cellular resolution. This would reveal whether healthy cardiomyocytes are using 65% of their energy for pumping function versus other cellular maintenance processes.
Such imaging could identify when heart metabolism shifts away from healthy patterns and allow targeted interventions to restore proper energy allocation. While conceptually feasible, achieving subcellular resolution presents significant technical challenges.
Imaging metabolism with cellular resolution faces major obstacles: achieving sufficient spatial resolution to distinguish individual cells within the human body, and developing surrogates for metabolism that can be visualized. Since metabolism itself has no visual manifestation, specific tools must be created to enable visualization of metabolic features.
Exciting tools are being developed to image various metabolic features in cells. The integration of chemistry, bioengineering, physics, and computational approaches has dramatically improved our ability to observe biological processes, moving from crude blood flow measurements to voltage and calcium imaging.
Determining which metabolic parameters would best indicate whether a cell is healthy or unhealthy remains a key challenge. The goal is to measure these parameters non-invasively without requiring tissue removal. While difficult, experimental tools for measuring metabolism in mice and cell cultures continue to improve, enabling measurement of specific molecules, intermediates, products, and substrates at individual cellular locations.
Dogs and occasionally humans can detect cancer scent beyond chance levels, though the biological basis remains unexplained. A validated case exists of a woman who could smell Parkinson's disease as a musty scent. Spouses of Parkinson's patients, particularly wives, have retrospectively recognized similar scent changes.
These scents represent chemical compounds produced by altered metabolism. Just as blood chemistry differs between diseased and healthy individuals, breath chemistry may reflect systemic metabolic changes. Parents' remarkable ability to detect when something is "off" in infants through scent changes in stool or skin demonstrates similar sensitivity to metabolic alterations.
Excess energy leads to problems not only through excess body fat but through biochemical issues created by too much energy at the front end. Mitochondria overloaded with excess energy contribute to generation of reactive oxygen species - reactive forms of oxygen that damage proteins and nucleic acids.
This widely accepted hypothesis suggests that mitochondria with too much energy become susceptible to generating reactive species that damage the genome, create mutations, damage proteins, and contribute to various pathologies including aging. This concept of excess energy toxicity applies from the organism level down to individual cells and their mitochondria.
Cells face consequences for improper energy allocation, whether taking too much energy or failing to distribute it correctly. This principle extends from single-cell analysis to societal levels. The discussion emphasizes understanding mitochondria's role beyond energy production, including resource allocation for functions other than building more energy for cellular replication.
Future approaches to cancer should move beyond tissue-based classification to examine specific cellular processes that may be common across different cancer types, while considering the body as a constellation of micro-factories with varying health statuses.
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