Inside our cells are tiny engines that supply the energy to sustain life. These protein machines essentially burn our food \u2013 producing CO2 and harnessing the energy that is released to sustain growth, movement and even thought.<\/p>\n
Each year, roughly 1.6 million people worldwide are born with genetic diseases that disrupt these tiny cellular engines \u2013 making life difficult.<\/p>\n
\u201cMutations in these protein complexes are really devastating, and often lethal,\u201d says James Letts, an associate professor of molecular and cellular biology.\u00a0<\/p>\n
These genetic disorders, called mitochondrial diseases, are especially damaging to the tissues that have the highest energy needs \u2013 including the heart, brain, and muscles \u2013 and cause heart failure, weakness, muscle wasting, seizures, dementia, loss of hearing and sight, and difficulty walking or moving.<\/p>\n
\u201cRight now, we have no way to treat these diseases,\u201d says Letts, who is trying to understand how these protein machines work, in hopes of changing this. His work could also improve medical treatment for heart attacks and strokes. It might even lead to new treatments for diseases of aging like Alzheimer\u2019s and Parkinson\u2019s.<\/p>\n
James Letts, an associate professor of molecular and cellular biology, investigates how mitochondrial protein machines power life\u2014and how understanding them could lead to new treatments for disease. (Sasha Bakhter \/ UC Davis)<\/p>\n
Revealing vast structures<\/p>\n
The burning or oxidation of our food is central to life as we know it. In plants, fungi, and animals it happens in tiny sausage-shaped compartments called mitochondria that sit inside our cells. The chemical reactions are carried out by a series of protein machines called respiratory complex I, II, III, IV, and V, which are among the most complicated molecular structures known to science. The largest of them, complex I, is assembled from different proteins, comprising nearly 50,000 atoms.\u00a0<\/p>\n
Letts has spent his career trying to decipher the 3D structure of these machines, down to the position of every last atom.<\/p>\n
During his postdoctoral fellowship at the Institute for Science and Technology in Austria, he learned a new technique for doing this, called CryoEM, in which the delicate, origami-like protein machines are cooled and stabilized at temperatures colder than \u2013100 \u00b0C, then imaged with an electron microscope.<\/p>\n
Letts and others found that the complex I is shaped like a letter \u201cL\u201d when it is turned on, and it can turn off by relaxing into a wider angle, which opens up an important part of the machine \u2013 preventing the oxidation process from going forward.<\/p>\n
The diversity of life\u2019s machines<\/p>\n
After joining UC Davis in 2018, Letts refined his methods to map the respiratory complexes of species using ever smaller samples. This allowed him to determine the structures of respiratory complexes across far-flung branches of the evolutionary tree of life, to discover their differences and similarities.<\/p>\n
In 2020 and 2022, he published the structures of complex I for mung bean plants (Vigna radiata)<\/a> and for the single-celled protozoa Tetrahymena thermophila<\/a>, finding that each lacked some of the protein engine parts that are known in mammals \u2014 but contained others that were new to science.<\/p>\n \u201cWherever we look on the tree of life, we find something totally unexpected,\u201d Letts says.\u00a0<\/p>\n This led to an important discovery in 2023: he found that in fruit flies (Drosophila melanogaster)<\/a>, complex I can actually lock into an on or off position. This doesn\u2019t happen in mammals \u2013 and it inspired an idea for new medical treatments.<\/p>\n \u201cWe think we can engineer specific binder molecules that might let us turn complex I on or off,\u201d says Letts.\u00a0<\/p>\n Keeping complex I turned on could help people with some mitochondrial diseases, in which mutations cause this complex to turn off too easily \u2014 strangling a cell\u2019s energy supply.\u00a0<\/p>\n On the other hand, people experiencing strokes or heart attacks have the opposite problem: brain and heart tissues are severely damaged when blood flow is suddenly restored \u2014 a phenomenon called reperfusion injury. This happens because, as oxygen floods into the hypoxic tissues, complex I turns back on before the other respiratory complexes are ready. This spews out toxic peroxides and oxygen free radicals that kill and damage cells.\u00a0<\/p>\n \u201cIf you could hold complex I inactive for a little longer, you could potentially prevent much of that damage,\u201d says Letts.<\/p>\n The 3D structure of complex 1, a cellular machine assembled from 45 different proteins, encompassing 50,000 atoms. Complex I carries out critical steps in the oxidation of food molecules, supplying the cell with energy. Understanding its function could improve the treatment of heart attacks, strokes, and genetic disorders called mitochondrial diseases. (Letts Lab \/ UC Davis)<\/p>\n A new understanding of respiration<\/p>\n Letts has also found another potential strategy for treating diseases.<\/p>\n Years ago, he and colleagues discovered that respiratory complexes don\u2019t always operate separately. In living cells, multiple complexes often connect, forming even larger machines<\/a> called \u201csupercomplexes,\u201d which efficiently funnel molecules that are being oxidized from one complex to another.<\/p>\n \u201cDiscovering this was a big deal,\u201d Letts says. \u201cIt took a while to convince the entire field that this was true \u2013 but it completely changed our understanding of cellular respiration.\u201d<\/p>\n In February 2025, he and his colleagues reported that these supercomplexes might lead to new medical treatments.<\/p>\n