Where do we come from? This old question takes on a new meaning when we ask it from the perspective of a nucleus-containing cell of a eukaryote (an organism with a membrane-bound nucleus and organelles). Before there were eukaryotes, there were bacteria and archaea in a world without free oxygen, making their anaerobic living next to, and likely from, each other. In a singular, improbable event some 2 billion years ago, an archaeal cell picked up a bacterial cell and the two stuck together, giving rise to a primitive eukaryote containing an endosymbiotic bacteria that we now call mitochondria. Why the two cells decided to stick it out together remains a mystery, but having mitochondria around surely paid off for archaea. Whereas archaea in our oxygen-saturated world nowadays are mainly limited to hot springs, deep-sea vents, and various intestines, their endosymbiont-containing relatives gave rise to oxygen-breathing, complex, single-celled organisms and subsequently evolved into the full spectrum of multicellular life that can be found everywhere today. One might even go so far as to say that mitochondria are the linchpin of our existence and that without the decision made by these two different kingdoms (bacteria and archaea) to live together, there would be no one around asking questions such as “where do we come from?”
Interestingly, mitochondria are not only necessary to ask where we come from, but they, or better their DNA, are actually helpful in answering this very question. Mitochondria are passed from generation to generation through the maternal line. Fathers are not allowed to contribute to the mitochondrial genome of their progeny because mitochondria from sperm are actively destroyed by the ovum after fertilization. This seemingly unfair practice is now helping us to trace our genealogy through the use of mitochondrial genome types as far back as the mitochondrial Eve some 100,000 years ago somewhere in Africa.
Although they have lived together for some time already and depend on each other like an old married couple, mitochondria retain some independence. They still contain their own bacterial-type DNA and protein synthesis machinery and new mitochondria still come into existence only from old mitochondria. However, mitochondria outsourced a decent amount of manufacturing and now have a strong trade imbalance. More than 99% of their proteins are encoded by the host cell's nuclear DNA and are produced in the host's cytosol, at which point they then have to be imported into the mitochondria using sophisticated machinery. So, despite their independence, mitochondria are very much embedded into their host cell.
The success of this unlikely symbiosis may be explained by the biochemical benefit the host cell got out of the relationship. Back in the day, when oxygen was still sparse, mitochondria brought nice anaerobic biochemistry to the table. Nowadays, with plenty of oxygen around, mitochondria shifted gear; by using oxygen together with food stuff and cool biochemistry, they provide more than 90% of the adenosine triphosphate (ATP) that our energy-hungry bodies and brains so desire.
Looking at mitochondria as simple power stations churning out ATP does not do justice to these amazing organelles. They provide many other services. They are important for the generation of enzymatic cofactors such as iron–sulfur clusters for many cellular enzymes and heme production for hemoglobin. Ironically, our red blood cells, which are rich in said hemoglobin, decided to divorce mitochondria and eat them during their formation, but mitochondria were able to return the favor. Many forms of programmed cell death, or apoptosis, start with mitochondrial permeabilization and the release of mitochondrial factors into the cytosol. This gives mitochondria a gate keeper role in life-or-death decisions during embryonal development, where the right cells have to die to form our bodies; cancer development, where the wrong cells did not die; and neurodegeneration, where the wrong cells die.
Looking into our bodies to where mitochondria have an especially important role, we find the eye. The retina is arguably the most energy-hungry tissue in our body, with a lot of mitochondria in photoreceptors and retinal ganglion cells. Even among energy-hungry neurons, retinal cells stand out. When looking at the distribution of mitochondria in the retina and optic nerve (Figure 1), we find a curious gradient across the lamina cribrosa. Retinal ganglion cells are packed with mitochondria before the lamina, whereas mitochondrial content is lower after the lamina. Because the light has to pass through the whole retina to reach photo-receptors, anything opaque in the light path would be counterproductive. One way for neurons to skimp on energy expenditure is to wrap themselves into an insulating myelin sheath and use saltatory conduction between the nodes of Ranvier. Because myelin is opaque, this is not an option for retinal cells. The lack of myelin is a prime reason for their huge energy consumption, and hence the need for the high mitochondrial density.
Mitochondrial distribution in the eye. A section of a human eye was stained using antibodies raised against subunit IV of cytochrome C oxidase. The brownish color indicates the presence of mitochondria. (A) Please note the abrupt change in mitochondrial content (arrow) once the optic nerve is formed by the retinal ganglion cell axons. (B) Also note the strong mitochondrial staining in the different retinal layers. ILM = inner limiting membrane; NFL = nerve fiber layer; GCL = ganglion cell layer; IPL = inner plexiform layer; INL = inner nuclear layer; OPL = outer plexiform layer; ONL = outer nuclear layer; PS = photoreceptors (Image courtesy of Prof. Peter Meyer, Basel, Switzerland.)
The unique features of mitochondria make for interesting disease patterns when something goes wrong. Mitochondrial diseases caused by mutations in nuclear-encoded genes, such as autosomal dominant optic atrophy, follow the normal Mendelian pattern of inheritance. However, diseases caused by the mutation of mitochondrial DNA, such as Leber's hereditary optic neuropathy, are inherited in a non-Mendelian manner and transmitted through the mother to her off-spring. Leber's hereditary optic neuropathy has other interesting features besides maternal inheritance. Mothers and their daughters carrying Leber's hereditary optic neuropathy mutations experience vision loss approximately eight times less frequently when compared to their sons or brothers. Besides this clear, potentially hormone-related gender bias, Leber's hereditary optic neuropathy also has a strong environmental component, with certain drugs, cigarettes, and alcohol identified as triggers of the optic neuropathy.
Beyond these clearly ophthalmic conditions, many other inherited diseases affecting mitochondrial function have a visual component. Charcott-Marie-Tooth 2A, caused by mutations in a nuclear-encoded mitochondrial morphogen, presents not only with peripheral neuropathy, but also with visual impairment. Similarly, MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like Episodes) and MERRF (Myoclonic Epilepsy associated with Ragged Red Fibers) are linked to vision loss. Mitochondria are not only the main culprit in inherited diseases, but mitochondrial dysfunction as a result of age, genetic background, and environmental factors is also to blame for diabetic retinopathy, age-related macular degeneration, and glaucoma.
Even in the face of these problems, the 2 billion-year marriage between archaea and bacteria is still going strong and, despite more than 150 years of mitochondrial research, there is still more to discover about this old married couple and its quarrels, struggles, failures, and triumphs.
- Ernster, L & Schatz, G. Mitochondria: a historical review. J Cell Biol. 1981;91:227s–255s.
- Karbowski, M & Neutzner, A. Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathol. 2012;123:157–171.