Evolutionary biology

Essence of mitochondria

For years, a unicellular creature called Giardia has occupied a special place in biology because it was thought to lack mitochondria. But it does have them — though tiny, they pack a surprising anaerobic punch.

All known life-forms are either prokaryotes or eukaryotes; there is nothing in between. Eukaryotic cells have a nucleus and compartments that are surrounded by two membranes, but prokaryotic cells never do. The prokaryotes came first; eukaryotes (all plants, animals, fungi and protists) evolved from them, and to this day biologists hotly debate how this transition took place, with about 20 different theories on the go1. In most textbook accounts, an ancient prokaryotic lineage supposedly evolved a nucleus, giving rise to a eukaryote, which then acquired mitochondria — the double-membrane-bounded powerhouses of eukaryotic cells. A cornerstone of this view has been the single-celled eukaryote Giardia intestinalis, which many consider to be a primitive intermediate2,3, a 'living fossil' from the time of the prokaryote-to-eukaryote transition, because it possesses a nucleus but lacks mitochondria. Or so we thought.

The paper on page 172 of this issue will surprise many people. There, Jorge Tovar and colleagues4 show that Giardia (Fig. 1) does have mitochondria after all. They are highly reduced, and are called mitosomes. Unlike the mitochondria familiar to most biologists, Giardia's mitosomes do not generate ATP (energy). Rather, they are factories for the assembly of iron–sulphur (Fe–S) clusters, which Giardia requires to make ATP. These findings mark a turning point for views of early eukaryotic and mitochondrial evolution: Giardia's place as an intermediate stage in standard schemes of eukaryotic evolutionary history2,3 is no longer tenable.

Figure 1: Mitochondria where least expected.
figure1

HOSSLER, CUSTOM MED. STOCK PHOTO/SPL

Giardia has been the textbook example of a single-celled eukaryote that lacks mitochondria. Now, with the paper by Tovar and colleagues4, it becomes a prime example of an anaerobic eukaryote that possesses mitosomes — highly reduced mitochondria that do not function in core ATP synthesis, but are essential for the assembly of iron–sulphur clusters. The image is about 100,000 times life size.

Giardia intestinalis (formerly G. lamblia) is a pathogen that shuns oxygenated environments and causes diarrhoea when it infects the human intestine. Like all cells, it requires a constant supply of ATP. Treatments for Giardia infection exploit the fact that its ATP-synthesizing biochemistry differs from ours. Whereas human cells make their ATP in mitochondria and require oxygen to do so, Giardia makes all of its ATP in the cytosol with the help of simple anaerobic pathways5,6. Several enzymes of Giardia's ATP-generating machinery contain Fe–S clusters5,6,7,8,9, which are ubiquitous cofactors in the electron-transfer reactions involved in ATP production. They are essential for the parasite's survival. Among Giardia's proteins that contain Fe–S clusters are hydrogenases7,8,9, ferredoxins and pyruvate:ferredoxin oxidoreductase5,8,9 (PFO, which incidentally is the target for anti-Giardia drugs).

In other eukaryotes — yeast and humans, for example — the synthesis of Fe–S clusters always begins in mitochondria10. But if, as almost everyone believes, Giardia lacks mitochondria yet has Fe–S clusters, where are the clusters synthesized? Tovar et al.4 have investigated this question, and find the answer to be that they are made in curious little membrane-bounded structures, several dozen of which are present in each Giardia cell. These organelles are surrounded by two membranes, a decisive observation that leaves only two reasonable possibilities as to what the organelles might be. This is because, in a century of delving into cells, biologists have discovered only two kinds of organelle that are surrounded by a double membrane: chloroplasts and mitochondria.

Chloroplasts are the organelles of photosynthesis in plants, and are descendants of cyanobacteria (photosynthetic prokaryotes) that, deep in evolutionary history, took up residence inside a eukaryotic host, forming a symbiotic partnership. But the Giardia organelles are almost certainly not chloroplasts, because no trace of chloroplast-specific biochemistry has ever been found in this protist. So are they mitochondria? Indeed they are.

Mitochondria are hallmarks of eukaryotic cells, and can be traced to another prokaryote — an α-proteobacterium11 — that took up residence in its host long before chloroplasts arose. Mitochondria comprise a diverse family of organelles, including many anaerobic forms12. Most notable among these are hydrogenosomes, hydrogen-producing forms of mitochondria discovered 30 years ago by Miklós Müller. As Tovar et al.4 explain, mitosomes are the most recent addition to the mitochondrial family of organelles. They are small, functionally reduced forms that were first found in the amoeboid parasite Entamoeba histolytica13 and the pathogen Trachipleistophora hominis14 (which belongs to a group of fungi called microsporidia). Before those reports, Entamoeba and microsporidia were thought to lack mitochondria altogether. Now mitosomes appear in Giardia, too, and we have the first direct glimpse of their function.

The biochemical role of the mitosome can hardly be core ATP synthesis. That occurs in the cytosol in both Entamoeba5 and Giardia5. And it is uncertain that microsporidia even make their own ATP, because they can steal it from the cells that they infect15. Tovar et al.4 show that, instead, the Giardia mitosomes harbour critical enzymes of Fe–S cluster assembly. Furthermore, cell fractions enriched for the organelle assemble Fe–S clusters in vitro. This pins a function to the mitosome in Giardia and is a major advance in understanding.

Possibly, Giardia assembles Fe–S clusters in mitosomes for the same reason that yeast and humans assemble them in mitochondria: the process is very oxygen-sensitive. The mitochondrial matrix (the space inside the organelle) is the most oxygen-poor compartment in oxygen-respiring cells because oxygen is consumed in the surrounding membrane. Lloyd et al.16 have shown that Giardia possesses organelles that accumulate mitochondrion-specific dyes and that can transfer electrons from donors to acceptors, which could easily include oxygen. But it remains to be seen whether the organelles observed by Lloyd et al.16 and Tovar et al.4 are identical.

Although mitochondria are usually considered to be oxygen-dependent, Giardia's tiny mitochondria have an anaerobic function (Fe–S cluster assembly) in the synthesis of oxygen-sensitive proteins such as hydrogenase and PFO, which are normally found in hydrogenosomes1,4,5,6,7,8,9,12. Eukaryotes diversified while the oceans were largely anoxic17,18, so these anaerobic functions are most easily seen as biochemical relicts of the mitochondrion's anaerobic past. Such anaerobic relicts are abundantly preserved in diverse eukaryotic lineages today9,12.

We know that mitochondria arose as intracellular symbionts in the evolutionary past11. But in what sort of host? That question still has biologists dumbfounded1. In the most popular theories, Giardia is seen as a direct descendant of a hypothetical eukaryotic host lineage that existed before mitochondria did2,3. But Tovar and colleagues' findings4 show that Giardia cannot have descended directly from such a host, because Giardia has mitosomes. So our understanding of the original mitochondrial host is not improved by these new findings, but our understanding of mitochondria certainly is. In its role as a living fossil from the time of prokaryote-to-eukaryote transition, Giardia is now retired. But it assumes a new place in the textbooks as an exemplary eukaryote with tiny mitochondria that have a tenacious grip on an essential — and anaerobic — biochemical pathway.

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Correspondence to Katrin Henze or William Martin.

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Henze, K., Martin, W. Essence of mitochondria. Nature 426, 127–128 (2003). https://doi.org/10.1038/426127a

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