Catalog of mitochondria across life’s family tree unearths new roles for the cell’s powerhouse

A research consortium that includes investigators from Mass General Brigham has generated the broadest look yet at the proteins that make up mitochondria, capturing the organelle’s diversity across multiple branches on the tree of complex life. With major contributions from Broad Institute scientists as well as its Proteomics Platform, the consortium generated and analyzed the mitochondrial proteomes of one plant and five single-celled pathogens that affect millions of people globally every year. Their results reveal unexpected new functions of the organelle, clues to its origin and role in the evolution of complex-celled organisms known as eukaryotes, and potential new drug targets for neglected tropical diseases.

The MitoCarta Tree of Life project was led by scientists at the Broad Institute, Mass General Brigham, Harvard Medical School (HMS), Harvard T.H. Chan School of Public Health, and Boston University Henry M. Goldman School of Dental Medicine. Their findings appear in nine scientific papers and a commentary article in Cell and related journals.

“With this consortium, we’ve repurposed everything we’ve learned over the last 15 years characterizing the mammalian mitoproteome to rapidly and diligently build out these inventories, creating a foundational resource for a new field of comparative mitochondrial biology,” said project leader Vamsi Mootha, MD, an investigator in the Department of Molecular Biology at Mass General Brigham. Mootha is also an institute member at the Broad; professor of systems biology at HMS; and a Howard Hughes Medical Institute (HHMI) Investigator.

In work led by team member and Harvard MD-PhD student Michael Chen, MSc, MPP, the researchers compared the data on six organisms along with the existing human and yeast inventories. They discovered many mitochondrial proteins in multiple pathogens that are missing from human mitochondria, representing potential targets for new drugs to treat tropical diseases.

The researchers also used the new data to explore a longstanding scientific mystery about whether mitochondria originated early or late in eukaryotic evolution. Using the new data to retrain a machine-learning based tool and predict the mitoproteomes for hundreds of untested species, the scientists reconstructed the timeline of when various organelles first appeared. Their analysis supports the notion that mitochondria appeared relatively late, after the ancestral eukaryote already had developed other complex parts.

The other papers focused on analyses of individual organisms. In one study, the team catalogued the mitochondrial machinery of Giardia, which causes a diarrheal disease, contains a mere 59 proteins and lacks energy-producing capabilities, making it more of a “remnant” mitochondrion that further challenges the narrow view of the organelle as simply a powerhouse.

For another study, they developed new methods to study the mitochondria of Babesia, a tick-borne pathogen behind a malaria-like illness that's spreading in New England due to climate change. Importantly, those methods may also work for related pathogens, such as those that cause malaria and toxoplasmosis.

“This project is one step in the larger scientific effort to use the existing diversity on Earth as a steppingstone toward answering one of the deepest questions: How did complex life evolve on our planet?” said team member Sarah Calvo, a senior computational scientist at the Broad and Mass General Brigham.

In addition, more than half of the proteins in these catalogs have unknown functions, so future studies may one day reveal even more clues to what makes human life, and that of all complex organisms on Earth, possible.

The data produced in these studies is freely available at mitocarta.org.

https://assets.massgeneralbrigham.org/adobe/assets/urn:aaid:aem:c5dd7a65-3ba2-4eea-96b9-6b048148fcda/as/vamsi-mootha-800x1100.avif?assetname=vamsi-mootha-800x1100.jpg&originalImageWidth=800&originalImageHeight=1100

Vamsi Mootha, MD