Science1 publisher2 min readPublished
MitoCarta's survey of five parasites and a plant finds proteins absent from human mitochondria
Broad Institute-led researchers have catalogued mitochondrial proteins in one plant and five human parasites across nine papers in Cell and related journals. Parasite proteins that human mitochondria lack give neglected tropical disease programs a first list of candidate drug targets to test.
The Scientist · Science desk
What happened
- The consortium, seven labs and 25 researchers assembled in 2022, focused on the model plant Arabidopsis and five parasites that cause human disease.
- Mass spectrometry at the Broad Institute determined which nuclear genes encode proteins that end up in each organism's mitochondria.
- A reconstructed timeline supports mitochondria arriving relatively late, after the ancestral eukaryote had already developed other complex parts.
- Giardia's mitochondrion holds just 59 proteins and cannot produce energy, so the researchers class it as a remnant organelle.
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Why it matters
- constraint Absence from human mitochondria does not rule out a related human protein elsewhere in the cell, so each candidate still needs selectivity and essentiality tests before it is a real drug target.
- constraint The late-origin timeline can be only as firm as the retrained predictor is on lineages unlike the six it learned from; directly measured proteomes from distant species would confirm or break it.
- precedent The 2008 mammalian MitoCarta was later used to find genes behind metabolic disease and neurodegeneration, and the plant and parasite catalogues are set up for the same kind of gene hunting.
The drug-target finding comes from a comparison led by Michael Chen, a Harvard MD-PhD student, who set the six new inventories against existing human and yeast catalogues [11]. It turned up many mitochondrial proteins in multiple pathogens that human mitochondria lack [11]. The published summary does not say how many candidates there are or which of the five parasites carry them.
The evolutionary result reaches further than the measurements do. The comparison rests on eight catalogues: the six new ones plus the human and yeast references [2]. To go beyond them, the team retrained a machine-learning tool on the new data, predicted mitochondrial proteomes for hundreds of untested species, and reconstructed from those predictions when various organelles first appeared [12]. Prediction is the only practical route into this question. The bacterium that became the mitochondrion was engulfed about 2 billion years ago [5], and an ancestral cell that old cannot be put through a mass spectrometer. I think the design fits the question, and I'd treat the late-origin timeline as a well-supported hypothesis.
Giardia's count is about 5 percent of the 1,100 proteins in the 2008 mammalian MitoCarta inventory, roughly one-nineteenth [6][1]. The two numbers come from different organisms and different generations of instruments, so the ratio gives scale and little more. The more striking detail is function. Mitochondria are described as the producers of chemical energy for eukaryotic cells [5], and Giardia's organelle produces none [14].
Vamsi Mootha, who leads the project, described the catalogues as a base for further work. "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," he said [4].
Namrata Udeshi, senior director of proteomics at the Broad Institute and one of the consortium's principal investigators, credited the instruments. "The speed and scale of this project would not have been possible without the platform's expertise in state-of-the-art, next-generation proteomic technology," she said [10].
What to watch
- A count of the pathogen proteins missing from human mitochondria, broken down by parasite, from the Chen comparison paper.
- Knockdown or chemical screens showing whether any of those candidate proteins is essential for parasite survival.
- Newly measured mitoproteomes from lineages outside the training set, checked against the retrained predictor's calls.