Mitochondria and the Electron Transport Chain (Part 6)
Complex III, the Q Cycle, and Cytochrome b (MT-CYB) gene mutation
Image 1 - complex III transfers electrons to complex IV via cytochrome c. In contrast to complex I and II, much of complex III is embedded within the inner mitochondrial membrane. However, a portion of it is still exposed to molecular oxygen within the mitochondrial matrix.
Complex III (ubiquinol-cytochrome c reductase or cytochrome bc1 complex) is multi-protein enzyme complex that transfer electrons (e⁻) from reduced CoQ10 (aka ubiquinol) to cytochrome c. Cytochrome c, sitting between complex III and complex IV, is uniquely positioned near the outer leaflet of the inner mitochondrial membrane (IMM) for electron transfer from complex III to complex IV. The following image shows Cyt-c (cytochrome c) as the transferring protein for electron distribution to complex IV.
Image 2 - the 5 protein complexes of the electron transport chain. ATP synthase is the last complex which forms adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate (Pi).
Mitochondrial DNA (mtDNA) mutations in the cytochrome b gene (MT- CYB) constitute a major cause of complex III deficiency. This genetic disorder can lead to a wide range of neuromuscular conditions, along with encephalomyopathy, and cardiomyopathy. Additional features include acidosis, muscle weakness, myoglobinuria, exercise intolerance, epilepsy, and vision loss. Leber hereditary optic neuropathy (LHON), which is a maternally inherited disease causing acute to subacute loss of central vision from optic nerve degeneration, is linked to MT-CYB mutations.
Image 3 - Leber hereditary optic neuropathy (LHON) - https://www.openmed.co.in/2021/10/leber-hereditary-optic-neuropathy.html.
Complex III (ubiquinol-cytochrome c reductase or cytochrome bc1 complex)
Complex III is made up of two 11 protein subunits which are nuclear and mitochondrial encoded. Ten proteins come from nuclear genes and one protein (cytochrome b) from the mitochondrial genome. Here’s an overview of complex III:
Exists as two identical complexes, aka dimers:
Each part has 11 protein subunits = 22 total.
10 proteins from nDNA and 1 protein from mtDNA.
QH₂ (ubiquinol) is oxidized to Q (ubiquinone).
Beginning of Q Cycle (see below).
2nd most prevalent site in the ETC for e⁻ leakage and superoxide formation.
Image 4 - this is shows one of two identical protein complexes that make up complex III. Notice this protein complex contains CoQ₁₀, iron and sulfur (Fe-S cluster), and a unique protein grouping called cytochrome b. Cytochrome c is intimately linked to complex III as well for the transport of electrons to complex IV.
The Q Cycle
The Q cycle is a series of reactions where electrons (e⁻ ) are transferred from QH2 (ubiquinol) to cytochrome c (cyt-c) as part of the electron transport reaction. QH2 is a two e⁻ carrier molecular, whereas cyt-c can only carry one e⁻. The Q cycle takes place in complex III within the inner mitochondrial membrane. Because of the dimeric structure of complex III the individual protein monomers perform their own electron transfer allow to an independent cyt-c. This occurs from the presence of an iron-sulfur (Fe-S cluster) and specialized heme proteins (cytochrome c1 and cytochrome b complex). The overall function of the Q cycle allows for 4 protons (H⁺) to be translocated from the mitochondrial matrix into the intermembrane space (IMS).
Image 4 - the Q cycle is a series of reactions occurring within the protein monomers of complex III. Ubiquinol (reduced CoQ₁₀) is critical as it passes carries two electrons that need to be transferred to cytochrome c and used in the translocation of protons into the intermembrane space.
Additional Information About Complex III and the Q Cycle
Like complexes I and II, complex III contains an iron-sulfur (Fe-S) cluster. This cluster is involved in one of the electron transfer reactions of the Q cycle. To review Fe-S clusters and their vulnerability from oxidative stress and poor antioxidant capacity read article 5.
One of the electrons transferring via Fe-S is passed to cytochrome c1 and then onto to an oxidized cytochrome c (cyt-c) molecule. The acceptance of an electron to cyt-c transitions it into a reduced form which passes the e⁻ to complex IV. In this reaction, cyt-c after losing the e⁻ is once again oxidized, where it now is available to accept another electron within the Q cycle.
The second electron cannot be accepted by cytochrome c (which is only able to accept and transfer one electron at a time), so it’s passed to cytochrome b (via two groups - heme bl, heme bH). This reaction for the 2nd e⁻ is more complicated than electron one transfer to cyt-c and involves the formation of a semiquinone radical (Q•-). Ultimately, this reaction also allows for two protons from the mitochondrial matrix to aide in ubiquinol (QH2) generation, and the increase in active cytochrome c available for electron for its own e⁻ capture.
The cytochrome b component of the Q cycle is a recycling protein that allows both electrons on QH2 to be used effectively. Even though two QH2 molecules participate in the reaction (Q cycle), one is regenerated through cytochrome b. This is the considered the cyclic component of the Q cycle.
Keep in mind that cytochrome b is the only protein of complex III that encoded by mitochondrial DNA (mtDNA). Therefore, damage to the mitochondrial genome affecting MT-CYB or potentially production of cytochrome b or genetic mutations of this gene can lead to significant deficiency activity of complex III.
Supercomplexes (SC), aka respirasome, of the electron transport chain are recognized as an integration of function between various complexes, as opposed to each complex functioning independently of each other. These SCs, such as complex I-III, complex I-III-IV, or II-III, are integral for electron transport chain function with regards to stabilization and protection from degradation of the protein units. However, the SC can also make multiple protein complexes more vulnerable to damage with wide-spread oxidative reactions or nutrient deficiencies.
In my assessment of multiple MitoSwab Plus profiles, complex II-III is the most common deficiency. In autism it’s very common with approximately 90% of MitoSwab assessments from my practice showing low complex III activity. Complex I deficiency on the MitoSwab is the 2nd most common finding. To review a few cases of MitoSwab complex deficiencies check out these two Substack articles:
Conclusion
Complex III is critical in the electron transport chain for moving electrons to complex IV and the eventual production of ATP. The protein monomers of complex III are mostly encoded by nuclear DNA. However, the cytochrome b protein, which is necessary for optimal function of complex III, is encoded by the mitochondrial genome. Because of its iron-sulfur clusters, just like complex I and II, and its dependence on the presence of CoQ₁₀, complex III is vulnerable to malfunction in the presence of excess oxidative stress and nutrient deficiencies.
Cytochrome III also plays an important role in the innate immune system with regards to macrophage activity and the control of inflammation. This topic will be covered in a future Substack article.