New research reveals an unexpected way that mitochondria, the powerhouses of our cells, can shape our health by influencing the genes that dictate cellular behavior.

NIEHS researchers have discovered that when mitochondria experience a supercharged state — known as hyperpolarization — it can set off a cascade of changes in DNA methylation and gene activity. This unexpected connection between cellular energy dynamics and gene regulation could have far-reaching implications for human health. The findings were published April 25 in Nature Communications.

“Mitochondria do so much more than produce energy,” said Janine Santos, Ph.D., of the NIEHS Mechanistic Toxicology Branch and senior author of the study. “Our research shows that their membrane potential can serve as a signaling mechanism, directly impacting gene regulation. That can open a whole new means through which environmental chemicals that affect these organelles may be linked to so many diseases.”

Supercharged cell structures

Scientists understand that the tiny organelles known as mitochondria can lose their electrical charge when they stop working properly. But far less is known about what happens when their electrical charge becomes unusually high — a state called hyperpolarization.

In this cell-based study, Santos and her team found that chronic hyperpolarization does not boost energy production but instead triggers various cellular adaptations. These include changes to cell membrane composition and the epigenome, particularly the shuffling of methyl tags on DNA that affect how genes are turned on or off.

The researchers traced these changes to shifts in key membrane building blocks called phospholipids rather than to disruptions in metabolism or oxidative stress, as previously shown when mitochondria lose function.

Exposures and disease states

To explore how different chemicals affect mitochondria, the team used data from Tox21, a collaboration among U.S. federal agencies to improve chemical safety testing. One phase of the program screened 10,000 chemicals, including pesticides, food additives, contaminants, and medications, to assess their potential toxicity. As part of this screening, scientists identified chemicals that altered mitochondrial membrane potential. They discovered that approximately 1,000 chemicals caused depolarization, whereas — to the researchers’ surprise — about 300 led to hyperpolarization.

In this study, Santos and her team focused on trying to understand the meaning of hyperpolarization. They selected some of those chemicals, and using gold-standard methods, showed that they could chronically hyperpolarize cells. Most importantly, they showed that the chemicals caused the same adaptations that they genetically characterized. Notably, they examined telmisartan and nebivolol, two medications used to manage blood pressure. They also looked at annatto, a food flavoring common in Latin American cuisine (in Mexico, it is called achiote).

These findings suggest that long-term exposure to such substances could influence human health and disease outcomes by altering gene activity through mitochondrial signaling, even in the absence of mitochondrial dysfunction.

“We are only beginning to understand how environmental exposures affect mitochondria,” said Santos. “Our findings raise important questions about whether some substances could push cells into a state of sustained hyperpolarization, leading to potentially long-lasting epigenetic changes that significantly alter cell function.”

Going forward, Santos said it will be important to assess whether the effects seen in this cell-based study occur at real-world exposure levels that people routinely encounter.

Dialing it down

The study also points to new therapeutic strategies. By adjusting mitochondrial membrane potential, scientists may be able to develop treatments that alter gene activity in beneficial ways. This approach might be particularly useful for conditions characterized by mitochondrial hyperpolarization, such as pulmonary hypertension and ovarian cancer.