Mitochondrial Function

Mitochondria are sausage-shaped organelles which feature a smooth outer membrane and an involuted (pocketted) inner membrane (see inset in illustration below). The inner and outer membranes are fairly close together. The space between is referred to as the intermembrane space. The inner membrane contains the proteins and enzymes of the electron transport chain (Complexes I-V) which are responsible for oxidative phosphorylation (the generation of ATP from oxygen). The innermost space is called the matrix, which contains the many enzymes of the citric acid cycle (and the mitochondrial DNA).

The production of ATP is driven by the energy of oxidation. At its most simplistic level, hydrogen (a source of electrons) is combined with oxygen (which is electron-poor) to generate energy. In more detail, NADH electrons (donated to Complex I) are combined with atmospheric oxygen (provided to Complex IV) to pump protons (H+) from the mitochondrial matrix across the inner membrane into the inter-membrane space. The proton “pressure” is tapped by allowing the protons to flow back through Complex V to generate ATP.

In addition to the main electron transport path from Complex 1 to Complex III to Complex IV, there is a second path from Complex II to Complex III to Complex IV. The two paths converge at coenzyme Q, which serves as a mobile electron transfer agent linking Complexes I and II with Complex III. Complex 1 gets its electrons from NADH (reduced nicotinamide adenine dinucleotide), a niacin-derived nucleotide that is loosely associated with three dehydrogenase enzymes of the citric acid cycle that are distributed throughout the mitochondrial matrix.

Complex II gets its electrons from FADH2 (reduced flavin adenine dinucleotide), a riboflavin-derived nucleotide that is closely associated with succinate dehydrogenase, a flavoprotein enzyme that is localized on the inner surface of the inner mitochondrial membrane. Succinate dehydrogenase is the only enzyme of the citric acid cycle that is membrane bound. Each turn of the citric acid cycle generates three NADH and one FADH2. The three NADH feed Complex I and the one FADH2 feeds Complex II to keep the process of oxidative phosphorylation (oxygen-derived ATP production) at full flux. Each NADH molecule generates three ATP (one from Complex I, one from Complex III and one from Complex IV) and each FADH2 generates two ATP (one from Complex III and one from Complex IV) for a total of eleven ATPs per revolution of the citric acid cycle. Since the citric acid cycle generates one ATP by itself, a total of a dozen ATPs are produced per revolution.

Mitochondrial Energy Schematic

Our favorite way to explain the inner workings of mitochondria is by analogy to batteries and hydraulics. The energy (redox potential) of combining hydrogen with oxygen is analogous to the voltage of a big battery. The big battery's voltage is significantly larger than the sum of the three smaller battery's voltages (wired in series, positive to negative), so the big battery charges the smaller ones (I, III and IV). Each of the smaller batteries is wired to a small hydraulic pump which pumps fluid (protons) into a reservoir (the intermembrane space) which feeds a generator (V) which converts the force of the fluid into power (ATP).