For decades, scientists believed that order was key to efficiency. However, a new study reveals that within the bustling machinery of mitochondria—organelles responsible for producing adenosine triphosphate (ATP), the universal energy currency of cells—one of the most enigmatic components is a protein that appears anything but orderly. This discovery challenges long-held assumptions about cellular efficiency.
ATP is crucial for nearly every biological task, from muscle contraction to neural signaling, and is continually recharged through metabolism. This life-sustaining energy cycle relies on highly coordinated electron flows within respiratory supercomplexes. Nestled within these mega-assemblies is QCR6, a tiny ubiquitous protein found in bacteria, yeast, and humans. Its acidic, floppy tail has remained structurally unresolved for decades due to its disordered, mobile, and electrically charged nature.
A recent study published in Nature Communications by Abhishek Singharoy, associate professor at ASU’s School of Molecular Sciences, suggests that this very disorder may be the secret to making life run efficiently. “The biological significance of protein supercomplexes has remained contentious, particularly how they tune the shuttling of charge-carrier redox proteins along with cell membranes during biological energy conversion,” Singharoy explained.
Unraveling the Mystery of Supercomplexes
Supercomplexes, large assemblies of multiple protein complexes, were once primarily associated with photosynthesis but are now known to appear across various biological systems. Respiratory chains in bacteria, yeast, plants, and humans all build these molecular megastructures. Interestingly, their individual enzymes function just as well outside of these assemblies as within them. This raises the question: why form a supercomplex at all?
The answer lies not in enzymatic reaction speed but in how quickly substrates can find their way to the proteins that process them. Jon Nguyen, a former graduate student in the Singharoy lab and now a postdoctoral research associate at Michigan State University’s Plant Research Laboratory, explained, “For decades, a highly disordered protein, QCR6, in mitochondrial supercomplexes was thought to enhance electron transfer and ATP production. However, experimental methods have been unable to resolve the structure of QCR6 because of its acidic and flexible region.”
“Now, using computational methods informed by experimental data, we present a model. Our simulations reveal that this highly disordered protein actually lowers the energy barrier for the diffusion of electron carriers during electron transfer, thereby increasing overall energy-conversion efficiency.” — Jon Nguyen
From Disorder to Functional Efficiency
Chun Kit Chan, a postdoctoral research associate and shared first author of the study, highlighted the significance of their findings. “Efficient metabolism is key to an organism’s survival. In this study, we revealed that QCR6, a tiny, acidic domain of a yeast respiratory complex, can leverage its intrinsic disorder to hover over respiratory protein condensates and cooperate with the surrounding acidic membrane environment to provide a folding-unfolding-based, guided diffusion to electron-shuttling enzymes, speeding up intra-protein electron transfers—and thus metabolism-linked ATP production—by up to 30%.”
This new work pushes the idea even further. The team employed multi-resolution computational methods, entropy-maximizing molecular dynamics, Brownian diffusion simulations, and cryo-EM data to build the first proposed structural ensemble for QCR6’s elusive tail. What emerged was startling: rather than being a passive, floppy ornament, the disordered acidic region behaves like a molecular flycatcher.
QCR6’s acidic, flexible region forms a shifting corona around the respiratory supercomplex. Positively charged electron carriers, like cytochrome c, are electrostatically attracted to this zone. The mobile tail reaches, hooks, and shepherds the electron carriers toward the reaction centers, reducing the energy barrier for carriers to arrive at the correct location—making electron transfer faster and more reliable.
Evolutionary Insights and Broader Implications
Working with collaborator and School of Molecular Sciences Professor Kevin Redding, the team also mapped how QCR6-like proteins vary across evolution. Primitive organisms such as heliobacteria lack these highly acidic, mobile hooks. Instead, their cytochrome electron carriers are literally tethered to the membrane—like balloons tied to a string—to ensure they don’t drift away.
“The heliobacterial cytochrome c is linked directly to a membrane lipid, with a ‘leash’ between that attachment site and the cytochrome domain,” Redding explained. “Unlike mitochondria, these bacteria don’t have an outer membrane to keep everything inside; they link it physically, so the cytochrome cannot wander off.”
This evolutionary comparison reinforces the central claim: the QCR6 region is not accidental disorder but functional disorder—an elegant evolutionary innovation for optimizing electron-transfer traffic. The discovery reframes how we think about disorder in biology. Sometimes, chaos is not a flaw. Sometimes, it is a design principle.
From molecular recognition to reaction efficiency to overall cellular fitness, the consequences of this discovery ripple upward. Indeed, the team’s models predict—and experiments confirm—that cells can grow 30% faster when this mechanism is active. The study offers a new perspective on how proteins can gain functional power precisely by not having a fixed structure.
