Mitochondria, In One Sitting

1. What does a mitochondrion look like?

A mitochondrion is roughly 0.5–1.0 μm wide and 1–5 μm long — about the size of a small bacterium. It has two membranes:

• Outer membrane: smooth, fairly permeable, contains pores called porins that let small molecules pass.
• Inner membrane: highly folded into finger-like ridges called cristae. The folding multiplies the surface area five- to ten-fold and is where the energy machinery lives.

The space enclosed by the inner membrane is called the matrix. It is gel-like, packed with enzymes, and contains its own small genome (more on that below).

Useful analogy. Picture a deflated balloon (outer membrane) inside which a heavily-corrugated tube (inner membrane) has been folded back and forth like a radiator’s fins. The radiator’s surface is where heat—or in our case energy—is processed.

2. The cell’s energy currency: ATP

Cells run on a molecule called ATP (adenosine triphosphate). Hydrolysing one ATP into ADP + phosphate releases ~30 kJ/mol of energy that the cell uses to:

• contract muscles,
• pump ions across membranes (for nerve signals, kidney filtration, etc.),
• build proteins, DNA, and RNA,
• move organelles around the cell.

The headline number, which surprises everyone the first time they see it: a typical adult’s body produces and uses about 50 kg of ATP per day — roughly its own body weight. This works because at any moment only ~50 g of ATP exists; each molecule is recycled (made and used) about a thousand times each day.

About 90% of that ATP is made in your mitochondria. The other 10% comes from glycolysis in the cytoplasm. The mitochondria are doing nearly all of the heavy energetic lifting, in every cell, all the time.

Simulation: Energy demand and ATP turnover

3. How mitochondria make ATP — the big picture

Cellular respiration extracts energy from food in three stages:

1. Glycolysis (in the cytoplasm). Glucose is split into two pyruvate molecules. Net yield: 2 ATP. Pyruvate enters the mitochondrial matrix.
2. Krebs cycle, also called the citric-acid cycle (in the matrix). Pyruvate is oxidised to CO₂; the electrons are caught by carrier molecules called NADH and FADH₂.
3. Oxidative phosphorylation (on the inner membrane). The electrons from NADH/FADH₂ hop down a chain of protein complexes. The energy released is used to pump protons (H⁺) out of the matrix, building up a steep concentration and electrical gradient. Those protons are then allowed to flow back through a special turbine, ATP synthase, which uses the flow to forge ATP from ADP and phosphate. Net yield: about 26–28 ATP per glucose.

The total yield from one glucose is about 30 ATP — roughly fifteen times what fermentation alone would give. This is why oxygen-using cells dominate the planet.

4. The chemiosmotic idea

The detail that usually trips up undergraduates is how the chain of electron-transfer proteins ends up making ATP. The answer was given by Peter Mitchell in 1961 and won him the Nobel Prize in 1978. His idea, called chemiosmotic coupling:

1. Electrons hopping along the chain release energy.
2. That energy pumps protons (H⁺) from the matrix to the intermembrane space, building a gradient (more H⁺ outside, fewer inside, plus a voltage of about −180 mV).
3. The gradient is potential energy — like water held behind a dam.
4. ATP synthase is the dam’s turbine. Protons flowing back into the matrix rotate it physically. Each rotation forces ADP and phosphate together to make ATP.

The mathematical statement is the proton-motive force:\[ \mathrm{pmf} = \Delta\psi - \frac{2.303\,RT}{F}\,\Delta\mathrm{pH} \approx -210\,\mathrm{mV} \]For an undergraduate the take-away is simpler: a battery is built across the inner membrane, and the battery powers a molecular motor.

5. The rotary motor: ATP synthase

ATP synthase is one of nature’s smallest and fastest motors. It has two parts:

• F₀ — embedded in the inner membrane. Looks like a small wheel of 8–15 subunits. Protons binding on one side and releasing on the other push the wheel around.
• F₁ — the catalytic head, which projects into the matrix. As F₀ rotates, an internal shaft turns three catalytic sites in sequence, each doing one third of the work of making an ATP.

Speed: ~150–300 rotations per second. Three ATP per revolution. So a single ATP synthase makes around 600 ATP/s; a typical mitochondrion has thousands; a typical cell has millions. This is why the “50 kg of ATP per day” number is achievable. The whole construction was discovered by Paul Boyer (binding-change mechanism, 1997 Nobel) and visualised at atomic resolution by John Walker.

6. Where did mitochondria come from?

Mitochondria evolved from free-living bacteria that, ~1.5–2 billion years ago, were engulfed by a larger archaeal cell. Both partners benefited and stayed together — the bacterium got a steady food supply, the host got an energy producer that could pay the cost of building a complex eukaryotic cell. This is the endosymbiotic theory, proposed forcefully by Lynn Margulis in 1967.

The fingerprints of this bacterial origin are still everywhere in the mitochondrion. It has a circular genome (like bacteria); its ribosomes resemble bacterial ribosomes (which is why some antibiotics targeting bacterial ribosomes have side effects on mitochondria); its inner membrane lipid cardiolipin is otherwise found only in bacteria. It also still divides by binary fission. Module 0 of this course treats the topic in detail.

7. Mitochondrial DNA — you only get it from your mother

Most of your DNA (~3 billion base pairs) lives in the cell nucleus. But mitochondria have their own little genome: 16,569 base pairs, 37 genes, circular, one or several copies per organelle, hundreds to thousands of copies per cell.

Mitochondrial DNA (mtDNA) is inherited only from the mother. The sperm’s mitochondria are tagged for destruction shortly after fertilisation. So your mtDNA came from your mother, who got it from her mother, and so on. Genealogy in the maternal line: by tracking mtDNA mutations, geneticists have traced all living humans to a common female ancestor (“Mitochondrial Eve”) who lived in Africa ~150,000–200,000 years ago.

Mutations in mtDNA cause a class of genetic diseases (Leigh syndrome, MELAS, LHON, and others) that are inherited differently from typical Mendelian disease — passed down only by mothers, with severity that depends on what fraction of mtDNA copies carry the mutation.

8. Why mitochondria matter for health

Mitochondrial dysfunction is implicated in an enormous range of diseases:

• Inherited mitochondrial diseases: Leigh syndrome, MELAS (stroke-like episodes), LHON (sudden visual loss), Kearns-Sayre. Often present in childhood with neurological or muscle symptoms.
• Parkinson’s disease: dopamine neurons in the substantia nigra are unusually mitochondrially demanding; defective mitophagy (PINK1/Parkin pathway) causes a familial form. The pesticide MPTP triggered an outbreak of fast-onset parkinsonism in young people in California in 1982 by poisoning Complex I.
• Alzheimer’s disease: brain glucose metabolism drops years before clinical symptoms, suggesting mitochondrial decline.
• Heart failure: the failing heart switches its fuel preference from fatty acids back to ketone bodies; cardiomyocyte mitochondria turn over faster than the cells themselves.
• Cancer: Otto Warburg observed (1931 Nobel Prize) that tumours rely on glycolysis even when oxygen is plentiful; modern understanding is that this is a metabolic trade-off favouring biosynthesis over ATP yield.
• Aging: Polg-mutator mice (defective mtDNA polymerase) age prematurely. mtDNA mutations accumulate in long-lived post-mitotic cells (neurones, cardiomyocytes) over decades.

The 2010s saw the first generation of approved mitochondrial therapies: AAV gene therapy for LHON, elamipretide for Barth syndrome, mitochondrial replacement therapy (“three-parent IVF”) for inherited mtDNA disease. Modules 7 and 8 of this course cover these in clinical detail.

9. Mitochondria are dynamic, not static

In textbook diagrams mitochondria look like neat ovoid sausages. In real cells, viewed by live microscopy, they are constantly:

• Fusing (joining) and dividing (fissioning), forming ever-changing tubular networks.
• Travelling along microtubules to reach high-demand sites — the tip of an axon, the contracting muscle fibre, the immunological synapse.
• Being eaten by autophagy (“mitophagy”) when damaged, replaced by fresh ones from biogenesis.
• Releasing signals to the rest of the cell — calcium for signalling, reactive oxygen species in regulated bursts, cytochrome c when it is time for the cell to die.

In a healthy cell about ~1% of mitochondria are recycled per hour. The whole population turns over within a couple of weeks. This dynamic-equilibrium picture replaced the older static one in the 2000s and is the subject of Module 6.

10. Quick check — ten one-liners to retain

• Mitochondria make ~90% of your cellular ATP.
• You produce roughly your body weight in ATP every day.
• The energy comes from electrons donated by food.
• Electrons reduce O₂ to H₂O at Complex IV; CO₂comes from the Krebs cycle.
• The proton gradient across the inner membrane is the cell’s “battery.”
• ATP synthase is a rotary turbine that uses the gradient to make ATP.
• Mitochondria evolved from engulfed bacteria ~1.8 billion years ago.
• They have their own circular DNA, inherited only from the mother.
• Defective mitochondria cause inherited disease, contribute to neurodegeneration, heart failure, cancer, and aging.
• They form a constantly remodelling network in healthy cells — not static sausages.

11. Self-check questions

Hints: Q1: heart energy demand. Q2: electron flow stops, gradient collapses, NADH accumulates. Q3: heteroplasmy and threshold effect. Q4: the bacterial ancestry of mitochondrial ribosomes. Q5: heat is generated instead of ATP — the same mechanism brown adipose tissue uses to keep newborns and hibernators warm.

Where to next?

You are now equipped to follow the rest of the course. Modules build in roughly the order they are listed:

• M0. Origin & Endosymbiosis — the bacterial roots, in detail.
• M1. Ultrastructure — cristae and the architecture.
• M2. Mitochondrial Genome — mtDNA and heteroplasmy.
• M3. Oxidative Phosphorylation — complexes I–IV in molecular detail.
• M4. ATP Synthesis — the rotary motor up close.
• M5. ROS, M6. Dynamics, M7. Disease, M8. Therapies, M9. Brain mitochondria.

The graduate modules use the proton-motive-force equation, Marcus electron-transfer theory, and the language of biophysics — but every concept you need has its roots here.