Mitochondria – tiny, free-floating organelles inside cells – have long been defined by their ability to convert nutrients from food into energy. Likewise, many scientists have assumed that diseases linked mitochondrial dysfunction – including neurodegeneration, cancer and diabetes – occur when mitochondria can’t properly supply energy, which they do by making a molecule called adenosine triphosphate (ATP).
Now, a new Northwestern Medicine study led by Navdeep Chandel, PhD, challenges the common understanding that energy production is mitochondria’s most important function by deciphering the organelles’ other responsibilities. The findings were published in Molecular Cell. Postdoctoral fellow Inma Reyes, PhD, was the paper’s first author.
“We have uncovered that mitochondria have an essential role in regulating biological outcomes such as epigenetics, cell proliferation and adaptation to low-oxygen conditions independent of their ability to generate ATP,” said Chandel, who is the David W. Cugell Professor of Medicine in the Division of Pulmonary and Critical Care Medicine.
Scientists already knew that mitochondria have multiple functions, but this study is one of the first to show that these other tasks operate completely apart from the generation of ATP. In the past, attempts to disrupt mitochondria always ended up disrupting ATP production, too. Therefore, it was difficult to tell if a study’s results – say, alterations in gene expression or cell proliferation – were related to the biology of the mitochondria themselves or to their supply of ATP.
“The challenge has always been uncoupling mitochondrial function from the ATP,” Chandel said. “In this study we were able to accomplish it by genetically removing a whole set of proteins from mitochondria and then only reconstituting certain proteins. This allowed us to restore specific functions without ATP.”
By bringing proteins important for metabolism back to cells lacking mitochondrial DNA, Chandel’s team restored epigenetic function in cell culture. Bringing back proteins that allow mitochondria to generate molecules called reactive oxygen species restored cell proliferation and adaptation to hypoxia. All of this occurred without ATP, demonstrating that manipulating mitochondria’s energy function may not be the best target for combating diseases.
“There’s no evidence that mitochondrial ATP is necessary to sustain the life of an organism. How do you know it’s not the other functions of mitochondria we’ve uncovered that are behind it? Or behind diseases with impaired mitochondria?” said Chandel, who is also a professor of Cell and Molecular Biology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
In future research, his team plans use the new techniques to separate the distinct functions of mitochondria in in vivo studies.
This research was supported by National Institutes of Health (NIH) grants RO1 CA12306708, PO1AG049665, RO1 HL122062, T32 CA009560, T32 GM008061, T32 T32HL076139, T32 HL076139 and RO1 CA157996, the Ramon Areces Foundation of Spain, the Netherlands Organization for Scientific Research and Robert A. Welch foundation grant I17733.
