Mitochondria are often called the “powerhouses” of the cell, for their ability to efficiently use the air we breathe and the food we eat and package it into molecules called adenosine triphosphate (ATP)—the currency it takes to get a job done in the cell. As the primary supplier of ATP, the mitochondria keep our hearts beating, neurons firing, and muscles moving.
With Great Power Comes Great Responsibility
Recent scientific discoveries have shown mitochondria in a new light—as regulators not only of ATP supply but where it is used. Like balancing a budget, the cell must manage its resources and prioritize its activities in response to the situation or environment it is in. How does a cell know when to turn on and off cellular processes? The mitochondria are vigilant sensors that help the cell monitor environmental cues and changing energy demands. They actively influence the function and fate of cells by determining how resources are used.
In addition to producing energy, mitochondria help the cell break down dietary sugar, fat, and protein into smaller building blocks that can be used for other purposes. These other purposes include some of the most central aspects of a cell’s life, including activating the immune system and regulating cell death. As we age, cells increasingly struggle to extract energy, metabolize nutrients, or generate a robust immune response. Importantly, as mitochondrial function becomes less efficient over the course of aging, we all become increasingly susceptible to chronic diseases. It may come as no surprise, then, that defects in mitochondrial function have been observed across a wide variety of diseases, from well-known diseases like diabetes and cancer, to the orphan diseases that Reata is studying.
ATP: The Cellular Currency That Can’t Buy Everything
The survival of a cell depends on its ability to respond quickly and robustly to stress—be it injury, invasion, or infection. In certain immune cells, for example, mitochondria are one of the main switchboards for this response, turning on and off many processes that are adjusted in response to a stressor. When doing so, mitochondria shift metabolism to divert resources that would have been used to make ATP, to instead produce molecules that activate and amplify the inflammatory response. When this happens, ATP production by the mitochondria decreases. As one example, mitochondria modify some of the oxygen that would have been used to make ATP to instead form reactive oxygen species (ROS). Although ROS can directly tackle intruders, like bacteria, and promote inflammation to help swiftly eliminate the threat, they are notorious for their damaging side effects.
This metabolic shift is meant to be a temporary diversion. Once the threat has been eliminated, it is critical that the cells return to homeostasis—a balanced state where inflammatory processes are turned off, ROS are neutralized, and mitochondrial metabolism returns to ATP production. In many chronic, autoimmune, and genetic diseases, this “off switch” fails, and these damaging processes stay on, ultimately leading to tissue damage and the potential loss of organ function.1
Nrf2 and the Restoration of Cellular Health
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key coordinator of the return to homeostasis. Several molecules that are naturally produced during the resolution of inflammation are activators of Nrf2, underscoring the importance of a well-timed Nrf2 response in this restorative process.
Though Nrf2 is known to reduce ROS and suppress inflammation, its roles in restoring mitochondrial function on the road to recovery are more recent discoveries. Nrf2 increases efficient ATP production, helps remove damaged mitochondria, and increases the production of new healthy mitochondria. 2,3 By clearing the damaging byproducts of inflammation and supporting mitochondrial function, Nrf2 improves the ability of the cell to recover from cellular stress, and is invaluable to overall cellular health.
Helping Mitochondria Help Cells Better
As the major suppliers of ATP, mitochondria remain invested in using resources wisely over the course of a stress response. In response to a threat, mitochondria help the cell reprioritize activities to ensure destruction of the threat and survival of the cell. Accomplishing this requires a temporary shift toward inflammation and ROS production at the expense of efficient ATP production. To recover, the cell activates Nrf2 to restore proper mitochondrial function, reduce oxidative stress, and clear inflammation.
Reata’s lead investigational drugs were designed to harness the power of Nrf2 by increasing its activity. These Nrf2 activators are currently being evaluated in clinical trials for the treatment of patients with diseases that have key features—mitochondrial dysfunction, oxidative stress, and inflammation—in common. As improving mitochondrial function emerges as a promising therapeutic strategy, we believe the complex relationship between Nrf2 and mitochondria holds great promise for the treatment of disease.