May 4th, also known as Star Wars Day to obsessed fans like us, is less than a week away and only lasts for a mere 24 hours, but to quote Jedi Master, Obi-Wan Kenobi, “The Force will be with you, always”. The proton motive force (PMF), that is. Equivalent to electrical batteries are tiny structures or “organelles” in animal and plant cells known as mitochondria that strip negatively charged electrons from the chemical breakdown of food and relay them through the electron transport chain (ETC) to oxygen. This current of electrons or electricity, which flows through the mitochondria, catalyzes the pumping of protons. The key to the synthesis of adenosine 5’-triphosphate or ATP, the universal energy currency of all cells, is the transport of positively charged protons across the mitochondrial membrane, as shown in Figure 1.
Figure 1. Schematic of the Proton Motive Force
This proton motive force or ‘voltage’ is the biologic basis of all life on Earth—and, according to the Jedi Master, Qui-Gon Jinn, of all life in the galaxy too. Gui-Gon relates the Force to the presence of midichlorians, “a microscopic life form that resides within all living cells”, as he explains to a young, pre-Darth Vader Anakin Skywalker in the Phantom Menace. To the ears of many mitochondria-lovers or “mitochondriacs”, ourselves included, midichlorians sounds suspiciously like a cross between mitochondria and chloroplasts, the ‘solar panels’ in plants that also use the proton motive force to make ATP. The term, “proton motive force”, comes from its discoverer, Peter Mitchell FRS (Fellow of the Royal Society), the brilliantly eccentric British biochemist who outlasted his many detractors in the old guard of the scientific establishment to win the Nobel Prize in 1978. (By the way, the first letters in Peter Mitchell FRS spells PMF. Coincidence or not?)
Peter Mitchell’s counterintuitive PMF discovery was slow to catch on but, when it did, a revolution started—quite literally, in fact, as the biochemist, Nick Lane, has pointed out, since a protein in the mitochondrial membrane called ATP synthase that converts the flow of protons into ATP revolves or spins, like a motor.
A long time ago, in a galaxy not far away at all because it was this galaxy, the ancestors of our cells formed the most unlikely quid pro quo with some intracellular bacteria: energy production (and the regulation of other important activities like cell death, and cell signaling) in exchange for room and board. Out of this mutually beneficial, once-in-a-lifetime partnership, the modern cell was born. Over two billion years, these bacteria lost their independence and evolved to become the permanent multitasking ‘powerplants’ that we call mitochondria.
Woe betides those with impaired mitochondrial function. Solid organs, such as the heart, liver, kidney, and brain, depend on the proton motor force to generate enough ATP to carry out their specialized functions. As the PMF decreases, that is, as the batteries start to run down with aging, for example, the likelihood of disease or death increases, as shown below in Figure 2. This raises the question of whether it is possible to treat or reverse the ebb of proton flow, and, thereby, to stave off disease onset and progression? The answer, possibly, is yes through exercise and calorie restriction. These interventions may—emphasis on the word “may” since the science is far from definitive—improve the function and the number of the mitochondria, reduce the incidence of disease, and extend lifespan. In yeast, worms, fruit flies, and mice, but not necessarily humans, the FDA-approved drugs, metformin, and rapamycin, possibly because they reduce inflammation, may increase lifespan. Other drugs may act similarly and EpicentRx has plans to prevent or tackle diseases caused by dysfunctional mitochondria.
Figure 2: A Simplified Analogy of the Proton Motor Force as a Battery Charge Level and Its Relation to Health and Disease
With age the battery charge of the mitochondria runs down. Potential interventions to increase longevity and stave off disease include exercise, calorie restriction, and drugs like metformin and rapamycin.
So, three cheers for the mighty mitochondria! And, to all our fellow Star Wars superfans, here’s to a happy 4th in advance and, of course, may the proton motive force be with you, always.