Oxidative Phosphorylation Defects Trigger Hypermetabolism in Mitochondrial Diseases

Columbia University researchers have discovered that human cells with impaired mitochondria respond by kicking into higher gear and expending more energy. This adaptation—called hypermetabolism—enhances the cells’ short-term survival, but it comes at a high cost: a dramatic increase in the rate at which the cells age.

“The findings were made in cells from patients with rare mitochondrial diseases, yet they may also have relevance for other conditions that affect mitochondria, including neurodegenerative diseases, inflammatory conditions, and infections,” says Martin Picard, senior author on the paper published in Communications Biology this week. “In addition, hypermetabolism may be a key reason why most cells deteriorate as we get older.”

It has been assumed that mitochondrial defects would force cells to slow their metabolic rate in an effort to conserve energy. However, by analyzing metabolic activity and energy consumption in cells from patients with mitochondrial diseases, the researchers found that cells with impaired mitochondria double their energy expenditure. Moreover, re-analyzing data from hundreds of patients with different mitochondrial diseases showed that mitochondrial defects also increase the energetic cost of living at the whole-body level.

Although this energy boost keeps cells running, it also degrades the cell’s telomeres and activates stress responses and inflammation. The net effect accelerates biological aging.

“When cells expend more energy to make proteins and other substances essential for short-term survival, they’re likely stealing resources from processes that ensure long-term survival, like maintaining telomeres,” says Gabriel Sturm, lead author on this study.

This hypermetabolic state could explain why people with mitochondrial diseases experience fatigue and exercise intolerance, among other symptoms. “To make up for the extra energy use in your cells, your body ‘tells’ you not to overexert yourself, to conserve energy. We likely see the same dynamic as people age and their vitality diminishes,” Picard says.