How Mitochondria Control Metabolism: Jared Rutter

Many, many years ago, a free-living bacterium was swallowed by another cell and did not die. It stayed. Over unimaginable stretches of time it became a permanent tenant, then a partner, then simply a part of us. That bacterium's descendants are the mitochondria living in every cell of the human body today. Jared Rutter, a biochemist at the University of Utah and an investigator with the Howard Hughes Medical Institute, calls this an endosymbiotic event, a case of one cell absorbing another without digesting it.

"Mitochondria are believed to have been the result of an endosymbiotic event where a bacterium, a free-living bacterium, was engulfed by another cell, and in a way, kind of domesticated by that cell." — Jared Rutter [09:26]

That ancient merger left a fingerprint still visible in every one of us. Mitochondria carry their own small loop of DNA, shaped like a bacterial genome, separate from the main genome sitting in a cell's nucleus. Because sperm lose their cytoplasm at fertilization, that loop of DNA comes only from the mother (17:46). Every mitochondrion in a person's body is a copy of the ones passed down along an unbroken maternal line.

The textbook shorthand for mitochondria, "the powerhouse of the cell," is not wrong, Rutter says, just badly incomplete. The bigger idea he wants listeners to sit with is that the body does not really have one metabolism. What we call metabolism is the sum of roughly 30 trillion separate decisions, one happening inside each of our cells (04:37). A heart muscle cell, which never stops contracting, wires its mitochondria to squeeze out every unit of usable energy, called ATP, from whatever fuel arrives (22:36). A stem cell lining the gut, which must completely rebuild the intestinal lining every five to seven days, wires its mitochondria differently, using them to produce the raw material for new cells rather than energy (23:16). Even a single neuron manages this trade at scale: some projections stretch a full meter, and mitochondria physically travel down them to power nerve signaling at the far end (19:27).

The fork in the road

The hinge point for all of this is a small molecule called pyruvate, the leftover once a cell has broken down a molecule of glucose through a chain of reactions called glycolysis (32:52). Pyruvate has two possible fates. It can be pulled into the mitochondria and oxidized, essentially burned with oxygen, to extract maximum energy as ATP. Or it can be converted into lactate and exported, keeping its carbon intact so it can later become protein, DNA, or fat, the raw stuff of a new cell (85:12). Rutter frames the whole of cellular life as a constant negotiation between these two options: "Food can either be converted to energy or it can be converted to biomass" (35:13).

For decades, scientists knew mitochondria needed a doorway to let pyruvate in, but nobody could find it. That changed around 2008, when Rutter's lab, newly curious about unidentified mitochondrial proteins, began investigating two candidates present in every organism that has mitochondria, from yeast to humans. Working with fly geneticist Carl Thummel, whose lab built fruit flies lacking the genes, and testing the same genes in yeast and human cells, the team triangulated results across all three systems. A parallel effort by Jean-Claude Martinou's lab in Geneva reached the same conclusion. In 2012, both groups published the discovery of the mitochondrial pyruvate carrier, MPC, the specific protein pair, MPC1 and MPC2, that opens a hole in the mitochondrial membrane for pyruvate to pass through (53:19, 82:47).

Finding the doorway let Rutter's lab test what happens when it is bricked shut. Mice engineered to lack MPC everywhere die before birth, around 12 or 13 days of gestation, roughly two-thirds of the way to term (67:31). But newer tools allow researchers to delete MPC only in specific organs. Deleting it only in the heart produces a stranger, slower story: the animals live for weeks. When they eventually die, they die of heart failure, with hearts that have grown abnormally large (68:58). The cardiomyocytes are not short on ATP, since they can still burn fat perfectly well. What seems to happen, in Rutter's words, is that the cells make "a resource allocation decision that turns out to be pathological": unable to easily burn the glucose-derived pyruvate, they shift toward building instead, and the resulting growth is exactly the kind of structural problem seen in human heart failure (69:47).

When building wins that should not

Lactate has a branding problem. For most of the twentieth century it was treated as a waste product, the residue left when muscles run short of oxygen during hard exercise. Rutter, along with researchers like Princeton's Josh Rabinowitz, has helped show that framing is wrong. Lactate is an active fuel, and the heart in particular is very good at burning it.

"The heart is an omnivore. Fats, glucose, lactate, ketones, amino acids, it will make ATP out of just about anything that ATP can be made out of." — Jared Rutter [66:20]

That omnivorous quality matters because glucose regulation is a matter of life and death on very different timescales. Chronically high blood glucose, the hallmark of diabetes, causes damage over years. Glucose that drops too low can kill within minutes, largely because the brain depends on a steady glucose supply and has very limited ability to burn fat instead (65:21). The heart's willingness to eat almost anything, including lactate, is part of what keeps it beating through both feasting and fasting; under normal conditions it draws 70 to 80 percent of its energy from fat, with the remainder made up by glucose, lactate, and other fuels (63:51).

The same burn-or-build fork explains a finding that puzzled scientists for a century. In the 1920s, German scientist Otto Warburg noticed that tumor cells consume less oxygen than expected and concluded their mitochondria must be broken. That observation, now called the Warburg effect, is still accurate, but the interpretation was backward (94:22). Rutter's work suggests cancer cell mitochondria are not broken at all. They are simply reallocated: instead of burning fuel and consuming oxygen, they favor building new biomass, the proteins, membranes, and DNA needed to make another cancer cell (95:30). Cancer, in this telling, is a cell that has made the same building decision a heart cell makes when its MPC is disabled, except cancer often makes that choice deliberately, as part of an evolutionary strategy to divide faster and evade the immune system (98:46).

That evolutionary framing also explains why cancer drugs stop working. A drug that kills 99.9 percent of cells in a tumor can still fail if the surviving 0.1 percent carries a resistance mutation, since that fraction can simply repopulate the tumor (100:12). Rutter points to HIV treatment as a model for what comes next: just as triple-drug combinations make it nearly impossible for the virus to develop resistance to all three at once, cancer therapy may increasingly rely on combinations of drugs, chosen based on a tumor's specific mutations, that make simultaneous resistance far less likely (101:22).

The episode's opening claim ties all of this together. Mitochondria that take in more energy than a cell can use become prone to producing reactive oxygen species, unstable oxygen molecules that damage proteins and DNA (00:28). An "overpowered" mitochondrion, in Rutter's phrase, is not a stronger one. It is one pushed past the point where its resource allocation still works. Whether that imbalance shows up as a heart that grows itself into failure or a cell that builds itself into a tumor, the underlying arithmetic is the same: every cell, all the time, is deciding what to do with what it has, and there is no version of cheating that arithmetic for long.