These past few weeks, I have written about many different genetic disorders and risk factors that stem from inherited errors in the DNA or mistakes in the division of chromosomes. But this week, I want to pivot a bit to talk about disorders that originate in a special form of DNA called mitochondrial DNA (mtDNA). Most of the DNA in your cells is housed within the nucleus, a central organelle (literally “little organ”—organelles are the “organs” of your cell with their own specific function). The nucleus keeps the DNA separate from all of the enzymes and chemical reactions of the cell. DNA spends most of its life inside the nucleus until the nucleus breaks down at the start of mitosis or meiosis. But nuclear DNA isn’t the only type of DNA in the cell. Another group of organelles called the mitochondria contain their own set of DNA, the mtDNA, that is unique and separate from the nuclear DNA.
Mitochondria are the only organelles in human or animal cells that have their own DNA. Scientists believe that this is because mitochondria used to be independent cells that were “swallowed” by bigger cells. The ancient mitochondria formed a symbiotic relationship with the cell and evolved into the mitochondria we have today. Mitochondria are responsible for converting oxygen to energy that the cell can use (you may have heard the phrase “mitochondria are the powerhouse of the cell”). As such, disorders of the mitochondrial DNA often have disastrous consequences for cellular functioning.
In a literal sense, a “powerhouse” is a place where electricity is created, usually by burning fuel and converting the heat energy that is released into kinetic and then electrical energy. This process takes advantage of the chemistry of hydrocarbon combustion. Combustion requires a hydrocarbon fuel (like coal, petroleum, methane, alcohol, etc.), a supply of oxygen (this is why you can “suffocate” a fire or suffocate in a fire), and an initial source of heat (the spark). The energy stored in the chemical bonds of the hydrocarbon is released during combustion as heat and the carbons, hydrogens, and oxygens recombine to create byproducts of carbon dioxide (CO2) and water (H2O). Combustion is a highly exothermic reaction, meaning it produces more energy than it takes in. Depending on the fuel, combustion can produce large amounts of heat energy that can be converted into kinetic or electrical energy.
Coal combustion is a common source of energy
The process that mitochondria, the powerhouses of the cell, use to create energy—called cellular respiration—is actually much more complicated than the combustion and energy conversion that occurs in a real powerhouse. The full process of cellular respiration is a mess of chemical reaction cycles, protein pumps, and potential energy gradients (trust me—you never want to learn the Krebs cycle unless you have to). But, in terms of what it requires and what it creates, cellular respiration is actually quite similar to the combustion used in real powerhouses.
The first thing required for cellular respiration is a hydrocarbon fuel, in this case glucose. Glucose is harvested from food or fat stores in the body and distributed to cells through the bloodstream. Glucose can be processed into small amounts of energy without oxygen through a process called glycolysis. When there is no oxygen to continue cellular respiration, a process called fermentation occurs instead to regenerate the molecules needed to continue breaking down glucose. Yeast cells use glycolysis and fermentation to create their energy, which has the fortunate (for us) byproduct of alcohol. For humans, fermentation occurs often in the muscles during strenuous exercise (perhaps you just went for a run and as horrendously out of shape as you are, you simply cannot get enough oxygen in your lungs for your poor overworked muscle cells). Instead of alcohol, this form of fermentation creates the (much less fun) byproduct of lactic acid, which is responsible for the soreness you feel for days after a workout.
Glycolysis is all well and good, and it occurs independently of the mitochondria, but it doesn’t produce nearly enough chemical energy for a bustling and overworked human cell. The rest of the cellular respiration process occurs within the mitochondria and it requires that staple of combustion, oxygen. Cells are provided with a constant stream of oxygen transported from the lungs by the red blood cells. A break in this supply for too long can be catastrophic, leading to brain damage, organ failure, and eventually death (here’s your daily reminder to breathe).
Just like combustion, cellular respiration utilizes a hydrocarbon fuel (glucose), oxygen, and a small amount of chemical energy (required for glycolysis) to create carbon dioxide, water, and a large net yield of chemical energy. But what do I mean by chemical energy? Cells don’t have electrical grids like cities do, so what does energy actually mean in cellular terms? Turns out, cells store all their energy in a spring-loaded molecule called Adenosine Triphosphate (ATP). ATP is made of adenine (the base found in DNA) with a line of three phosphates (PO3) attached to it. The phosphorous-oxygen bond is so spring-loaded and full of potential energy that breaking the bond (removing one phosphate group) releases a good deal of energy that can do work in the cell.
Many chemical reactions in the cell aren’t spontaneous (they require more energy than they produce), but the cell is able to make these reactions happen by coupling them with the breakdown of ATP that makes up for the energy deficit. Once ATP is broken down into its inactive form, it has to be “recharged” through cellular respiration. Just as breaking a phosphate off of ATP creates energy, adding a phosphate back to ATP requires energy harvested from the breakdown of glucose. Glycolysis can only generate a net yield of 2 ATP molecules for every molecule of glucose. But with cellular respiration through the mitochondria, cells can produce up to 32 ATP molecules with a single molecule of glucose. For some simpler cells, glycolysis is enough to keep them going, but the incorporation of mitochondria into cells is one of the key events that made more complex life possible.
Considering the central importance of mitochondria in keeping the cell going, it isn’t surprising that defects in the mitochondria can be debilitating or fatal. For example, a variety of different mitochondrial defects result in Leigh Syndrome, a neurological disorder that often results in death before the age of three. The defects that result in Leigh syndrome can arise from genes in either the nuclear DNA or the mitochondrial DNA. Approximately 20% of individuals with with Leigh Syndrome have a mutation in the mtDNA.
Mitochondrial DNA, unlike nuclear DNA, is stored in a single circular chromosome that contains just 37 genes. Circular DNA is a hallmark of bacteria cells and other prokaryotes (organisms without a nucleus), which adds credence to the idea that mitochondria were once independent bacteria. Because mtDNA is stored in the mitochondria, its inheritance is also rather unique. When gametes fuse to form an embryo, 100% of the embryo’s organelles are provided by the mother’s egg. This means that all of your mitochondrial DNA comes directly from your mother. Scientists can use mtDNA’s strict maternal inheritance to easily trace bloodlines back generations.
A downside to the unique inheritance of mitochondrial DNA is that mothers with a mtDNA defect, like Leigh Syndrome, are pretty much guaranteed to pass it on to all of their children. Debilitating and often fatal, these defects often only lead to heartbreak for affected mothers intent on having children. In recent years, a controversial development in in vitro fertilization (IVF) technology has given mothers with mitochondrial DNA defects hope. The 3-parent baby method involves moving DNA from the parents into the nucleus of a donor egg with healthy mitochondria. Next week, I’ll write more about the process of IVF, the 3-parent baby method, and why this method is currently outlawed in the United States.
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