A Spoonful of Sugar Makes the Mitochondria Go Down

Part 2 of 7 — Inside the Power Plant: A Masterpiece You've Never Seen

Before I show you how sugar wrecks your mitochondria, I have to show you what mitochondria actually are. Not because I want to bore you with biology — I promise I will not — but because the wreckage I am about to describe in Part 3 only makes sense if you know what was being wrecked.

What I am about to describe is, in my professional opinion, the most extraordinary piece of engineering on planet Earth. We built skyscrapers. We built the internet. We landed a robot on Mars. None of these things, taken together, come within a parsec of the elegance of what is going on right now, this minute, inside the cells of the hand holding your phone. I tell my patients this and they look at me like I'm a religious nut. Then I show them what's actually happening and they get quiet.

Pay attention. The cathedral is about to come into view.

The Ancient Immigrants

Here is the strangest fact in cell biology, and it is one most people never learn: the mitochondria inside your cells are not human.

They are not, in any technical sense, part of you in the way that, say, your liver or your skin are part of you. They are descendants of an ancient bacterium that, somewhere around two billion years ago, got engulfed by a primitive single-celled organism. Normally, when a cell engulfs a bacterium, the bacterium is digested. This one wasn't. For reasons we will never fully know, the two cells struck a deal. The bacterium agreed to make energy for its host. The host agreed to protect the bacterium and feed it raw materials. They became permanent partners. Every multicellular organism alive today — every plant, every animal, every fungus, every blade of grass and every blue whale and every human being — descends from that one ancient, accidental partnership.

That is why your mitochondria carry their own DNA — separate from the DNA in your nucleus. It is called mtDNA, mitochondrial DNA, and it is the last surviving relic of the bacterium your ancient ancestor swallowed. You inherit it almost entirely from your mother (the sperm's few mitochondria are usually destroyed at fertilization). The genetic line of your mitochondria runs back, mother to mother to mother, in an unbroken chain that crosses every species of mammal, every species of vertebrate, every branch of the tree of life, all the way back to that primordial soup.

That is breathtaking. But it is also dangerous, and here is why.

The DNA in the nucleus of your cells — your "main" DNA — is treated like a national archive. It is wound around protective proteins called histones. It is organized into compressed structures called nucleosomes. It is surrounded by a sophisticated army of repair enzymes that constantly patrol the genetic code, looking for errors and fixing them. When a mistake happens, there are backup systems. Backups for the backups.

The mtDNA inside your mitochondria has almost none of this. It floats, essentially naked, inside the mitochondrial interior — right next to the furnace where the sparks fly. The repair machinery is minimal. The backups are limited. When mtDNA is damaged, the damage tends to stick.

This single fact — that the most vulnerable genetic material in your body sits in the most exposed location in the cell — is going to come back, in Part 3, as one of the cruelest tricks in the entire pathology of sugar damage. Hold it.

A heart muscle cell can hold five thousand mitochondria. A neuron, several hundred to several thousand. Across your whole body, the total mitochondrial population is something like a quadrillion — a thousand trillion of these tiny ancient bacteria, working together inside you, every second, to keep the lights on.

Now let me show you how they actually do it.

A Three-Stage Assembly Line

When you eat a piece of bread, or a bowl of rice, or a candy bar, or anything containing carbohydrate, your digestive system breaks the carbohydrate down to its simplest form: glucose. Glucose is delivered by your bloodstream to your cells. Inside each cell, the glucose then runs through a three-stage assembly line that ends, ultimately, with the production of ATP — the molecular currency of life.

Stage 1 happens in the cytoplasm — the jelly-like fluid that fills the cell outside the mitochondria. It is called glycolysis, which is Greek for "sugar splitting." A six-carbon glucose molecule is broken in half, into two three-carbon molecules called pyruvate. This stage produces a small amount of ATP — two molecules of it, which is barely worth mentioning — and, more importantly, it produces a few molecules of something called NADH.

NADH is one of those acronyms biology students dread. It stands for nicotinamide adenine dinucleotide, in its "reduced" or electron-loaded form. The chemistry is not the point. The point is this: NADH is a battery. A loaded battery, full of electrons, that the cell is going to deliver to the power plant. Picture a UPS truck pulling up to a power station with a stack of charged batteries in the back. That is what glycolysis produces. A small handful of charged batteries.

Stage 2 happens inside the mitochondrion. The pyruvate from glycolysis is shipped through the mitochondrial membrane, where an enzyme called pyruvate dehydrogenase — the "gatekeeper" — converts it into a smaller molecule called acetyl-CoA. Acetyl-CoA is a two-carbon fuel pellet. It enters a spinning wheel of eight chemical reactions called the Krebs Cycle (sometimes called the citric acid cycle, or the TCA cycle, after the German biochemist Hans Krebs who described it in the 1930s).

The Krebs Cycle is, on paper, a tedious diagram of chemical reactions that every premed student is forced to memorize and then forget. Forget the diagram. Just understand this: the Krebs Cycle is a battery-charging station. Every revolution of the wheel produces three more NADH batteries, one of a related battery called FADH₂, and one more ATP. And it produces, as exhaust, the carbon dioxide that you breathe out.[23]

Think of it this way. You ate glucose. The glucose got split, in glycolysis, into pyruvate. The pyruvate got fed into the Krebs Cycle, which spun and spun and spun and, every time it spun, kicked out a fresh batch of charged batteries. By the time the cycle is done with one glucose molecule, you have a substantial stack of charged batteries — NADH and FADH₂ — and a small handful of ATP. The serious payoff has not happened yet. We are about to deliver the batteries to the actual power plant.

The Turbines: Where the Real Magic Happens

Stage 3 is where it gets glorious. This is where I want you to slow down.

Inside the mitochondrion, the inner membrane — the one closest to the matrix where the Krebs Cycle is spinning — is not smooth. It is folded into elaborate ridges and valleys called cristae. Picture a mountain range crammed inside a tiny capsule. The folding is not decorative; it dramatically increases the surface area on which the next set of machinery can be embedded. Some mitochondria have so many cristae packed into their interior that the folds nearly fill the available space.

Embedded in this folded membrane are five enormous protein complexes, numbered I through V, collectively called the Electron Transport Chain or ETC.[5][6] The ETC is the actual power plant. The Krebs Cycle delivers batteries to it; the ETC drains the batteries to mint ATP.

Here is how it works, step by step. I am going to walk you through this slowly, because in Part 3 I am going to show you exactly where it breaks, and that will only make sense if you have first seen it work.

Step one. A loaded NADH battery, fresh from glycolysis or the Krebs Cycle, docks onto Complex I — the first of the five protein machines. Complex I rips the electrons off the battery, draining it. Those electrons enter the chain.

Step two. Complex I, having ripped off the electrons, uses the energy of that reaction to pump four hydrogen atoms (technically protons, hydrogen atoms stripped of their own electrons) from inside the mitochondrial matrix to the space between the inner and outer mitochondrial membranes. It is acting like a pump that is moving water uphill — moving protons against their natural gradient, into a small space where they will accumulate.

Step three. The electrons themselves, now stripped from the battery, are passed along to a small mobile shuttle molecule called Coenzyme Q10, or CoQ10. CoQ10 is the relay runner. It picks up the electrons from Complex I and carries them to Complex III. (Complex II also exists — it handles a different battery called FADH₂ — and it passes its electrons to CoQ10 as well. But it does not pump protons. Hold that detail; it matters later.)

Step four. Complex III takes the electrons from CoQ10 and pumps four more protons into the intermembrane space. The pile of protons is growing. Then Complex III passes the electrons to another mobile shuttle, this one called Cytochrome C. Remember the name Cytochrome C. I will be coming back to it. It is the canary in this particular coal mine.

Step five. Cytochrome C delivers the electrons to Complex IV. Complex IV is the cleanup crew. It takes the electrons, combines them safely with oxygen and protons, and produces water. This is, by the way, where the oxygen you breathe actually ends up — at Complex IV, becoming water, after having served as the final dumping ground for the electrons that powered your day.[6]

Step six — the grand finale. All those protons that have been pumped, one after another, into the intermembrane space — they are now sitting there under enormous pressure. The intermembrane space has filled up like water behind a hydroelectric dam. The cell calls this pressure the mitochondrial membrane potential — written by scientists as ΔΨm, "delta psi m," but I think of it as just the dam being full. The protons want desperately to flow back across the inner membrane to relieve the pressure. There is only one way for them to do that. They have to flow through Complex V.

Complex V — also called ATP Synthase — is the most beautiful machine in biology. It is a literal molecular turbine. The protons, rushing through it under pressure, spin a rotor. The rotor's mechanical motion is harnessed to stamp ATP, one tiny coin at a time, from the raw materials floating around in the matrix. Every spin of the turbine produces ATP. The pressure from the protons drives the turbine. The turbine mints the currency. The currency funds every transaction your body will undertake for the rest of the day.

One glucose molecule, run cleanly through this entire three-stage process, yields about thirty to thirty-two ATP. Compare that to the two paltry ATP produced by glycolysis alone. The mitochondria amplify glycolysis's output by a factor of fifteen. That is why you have them. That is what they exist to do.

And the system is staggeringly clean. When it is running properly, the electrons stay on the wires. The oxygen at Complex IV becomes water, not anything more reactive. The protons flow through the turbine, not around it. The waste products are carbon dioxide, which you exhale, and water, which you piss out. The fuel is glucose or fat. The output is energy. The mechanism is, for all practical purposes, a perfect microscopic power plant — designed by two billion years of evolution to do its job and shut up about it.

This is the machine. This is the masterpiece. This is what is humming, quietly and elegantly, inside every one of your trillion cells, right now, as you read this. It is the closest thing to magic that exists in the natural world, and it is in trouble.

Why Glucose, in Moderation, Is Fine

I want to pause here and make a point I will keep making throughout this series, because the world is full of voices that want to tell you sugar is poison and the answer is to eat zero of it, and that is not my position and it is not what the science says.

Glucose is the body's universal fuel. Your brain alone burns about one hundred twenty grams of glucose per day under normal conditions — that is the equivalent of about a thirty-cup-of-coffee dose of sweetener, just to keep your brain running.[112] Your red blood cells can only burn glucose; they do not have mitochondria and cannot use fat. Your fast-twitch muscle fibers, the ones that power a sprint or a heavy deadlift, depend on glucose. Your immune cells, when they are fighting infection, ramp up glucose burning enormously.

The cell was designed to handle glucose. The mitochondria were designed to burn it. When glucose arrives at a reasonable rate, in reasonable amounts, the entire three-stage assembly line I just described works beautifully. NADH and FADH₂ batteries are produced at a rate that the ETC can handle. Electrons flow smoothly along the wires. Protons get pumped, the turbine spins, ATP gets made, water and CO₂ are the only waste products. The antioxidant systems we will meet in Part 3 handle the small, normal trickle of sparks that any chemistry produces. The system is at equilibrium. There is no smoldering.

The catastrophe — and I am using that word with full clinical seriousness — is what happens when glucose arrives too much, too fast, too often.

That is what we will look at in Part 3. The exact mechanism. The first sparks. The flooded furnace. The way an overloaded assembly line begins, slowly at first and then very quickly, to set itself on fire.

But before we get there, one more thing.

The Mitochondrial Population Is Not Fixed

There is one more piece of biology you need to know before we go anywhere else, because it is the source of all the hope in this story.

The number of mitochondria in your cells is not fixed. It rises and falls in response to your behavior.

When you exercise — especially aerobic exercise sustained for more than about twenty minutes — a master regulator protein inside your cells, called PGC-1α (pronounced "P-G-C-one-alpha"), gets activated.[25][26][27] PGC-1α is the city planner. When it is active, it turns on the genes that build new mitochondria. New ones. From scratch. The cell literally manufactures more power plants in response to the demand signal that exercise sends. This process is called mitochondrial biogenesis.

A trained endurance athlete can have two to three times the mitochondrial density in their leg muscles compared to a sedentary person of the same age. Sustained cold exposure does it. Fasting does it. Ketones do it. Certain compounds do it. But the single most potent activator of PGC-1α we know — the closest thing to a fountain of youth that medicine has discovered — is exercise.[73][75][97]

This matters because the opposite is also true. When mitochondria are being damaged faster than they are being replaced, the population shrinks. And the conditions that damage mitochondria — chronic high blood sugar being foremost among them — also actively suppress PGC-1α.[26][57] The inflammatory cytokines triggered by sugar damage shut down the city planner.

So here is the situation we are walking into, in real biological terms. The modern Western diet is simultaneously (a) damaging the existing mitochondria, and (b) suppressing the construction of new ones. The factory is burning down, and the construction crew has been fired. That is why metabolic disease accelerates with age and with cumulative sugar exposure. It is not just that more damage accumulates over time. It is that the damage is happening in a system whose ability to repair itself has been deliberately disabled.

But — and this is the hope — when you stop the sugar flood, PGC-1α comes back online. The construction crew comes back. New mitochondria can be built. In the young, this is fast. In the old, it is slower, but it still happens. The system was never permanently broken. It was just being prevented from healing.

That is what we are going to build toward, all the way through to Part 7. The jungle can come back. But you have to stop burning it down first.

Where We Are Going

In Part 3, we go into the fire. I am going to show you exactly what happens, in molecular detail, when too much glucose arrives at once — when the assembly line gets flooded with charged batteries faster than the turbines can handle them. We will meet the reactive oxygen species. We will watch the sparks fly off the electron chain. We will see what happens when those sparks find iron, and we will meet the most destructive molecule produced in human biology: the hydroxyl radical. We will watch the scaffolding burn. We will watch the mtDNA — that vulnerable little bacterial relic — get blasted with mutations that will be passed down to every new mitochondrion the cell tries to build.

It is not subtle. It is not gentle. It is a forest fire in slow motion, happening, right now, in the cells of the average modern person eating the average modern diet. And the reason we, as a society, are not screaming about it from every rooftop is that the fire is invisible, and the damage takes decades to show up at the surface as the disease we recognize.

The fire is on. The smoke is real. Let's go look at it.

This is Part 2 of a 7-part series. Continue to Part 3: The First Sparks.