Intriguing findings in small studies of humans and in animal research have since directed scientists toward a closer examination of mitochondria’s involvement in other, more complex diseases—those with multiple genetic and environmental causes, including Parkinson’s, type 2 diabetes and cancer. The researchers suspected that smaller mutations in a series of nuclear genes that encode mitochondrial proteins, or slight mitochondrial defects stemming from environmental factors or even simple aging, could help trigger these diseases. Disabled mitochondria do a poor job producing energy, and that allows electrons to leak out of the electron transport chain and interact with oxygen inside the mitochondria, creating free radicals that further damage the mitochondria. Some mitochondria in a cell may completely shut down, while others function so poorly that they trigger a chain reaction of destructive events. The diseases that may result from this dimming and flickering are less immediately severe than those that are caused by mutations in mitochondrial DNA, but they may end up being just as deadly.
The link between mitochondria and Parkinson’s disease was discovered serendipitously in the early 1980s, when addicts began injecting a contaminated version of a euphoria-inducing drug called meperidine. In fact, the drug had been inadvertently poisoned by a meperidine by-product called MPTP. After the drug users developed symptoms strikingly similar to those of late-stage Parkinson’s, researchers found that MPTP inhibits mitochondria’s energy-producing machinery in neurons that make dopamine—the same neurons that are killed in Parkinson’s disease.
Since then, researchers have identified at least three nuclear genes whose proteins are associated with mitochondria. Preliminary evidence suggests that these genes are all involved in managing oxidative stress—the damage caused by free radicals. This points to a possible vicious cycle of deterioration in which mutations hinder the mitochondrion’s ability to generate energy while churning out higher levels of polluting ROS, which, in turn, tear up a cell’s protective membranes and further mutate mitochondrial DNA. The damaged mitochondria may create still more ROS, and the cycle continues.
If, indeed, oxidative stress is implicated in Parkinson’s disease, finding a way to relieve it might slow mitochondrial deterioration. Typically, antioxidant dietary supplements don’t help, probably because they can’t get through the mitochondrial membrane into the matrix, where free radicals are produced. To address that problem, Mike Murphy designed MitoQ with a positive charge so that it would be drawn in by the mitochondria’s negative charge.
Now the larger Phase II trials should show how well MitoQ, a powerful antioxidant, works in humans and help determine whether oxidative stress does play a major causative role in Parkinson’s—and, potentially, in a number of other diseases, including Alzheimer’s, amyotrophic lateral sclerosis (ALS) and even migraines. If MitoQ works for Parkinson’s, it might also prove effective against those other diseases.
In the case of type 2 diabetes, one of today’s most prevalent diseases, evidence for a possible mitochondrial link stems from the observation that mitochondria of diabetics have a reduced ability to produce energy. In 2003, Vamsi Mootha, a systems biologist at the Massachusetts General Hospital and the Broad Institute in Cambridge, decided to test whether a genetic approach, using a device known as a gene chip, could help isolate the problem. (Gene chips are quartz plates the size of a postage stamp spotted with every human nuclear gene, but not mitochondrial DNA. Manufacturers chemically attach more than 20,000 bits of DNA at specified coordinates on the plate.)
In his study, Mootha and his team poured a batch of RNA—the intermediary molecule DNA uses to make proteins—from the muscles of diabetics over 17 chips. To 18 others they applied RNA from the muscles of nondiabetics. He knew that if the RNA stuck to the DNA on the chip and fluoresced under a special light, the genes were actively producing proteins.
The results were striking. The dots for genes involved in energy production pathways—and linked to mitochondria—were much dimmer in diabetics than in those without the disease. It appeared whole sets of energy-production genes were associated with diabetes. “No single gene showed a striking difference in expression between the diabetics and the controls, probably because diabetes is a complex disease,” Mootha says. “Rather, we’re seeing a general decline in mitochondrial numbers and activity,” suggesting diabetic muscles can’t produce energy as well as nondiabetic muscles.