Mitochondria

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The mitochondria generate the energy that is needed to power the functions of the cell, but also participate in several other cellular functions, including apoptosis, cell cycle control and calcium homeostasis. They are distributed throughout the cytoplasm of the cell, each organelle enclosed by a double membrane, the inner one forming the characteristic folds known as cristae. Mutations causing mitochondrial dysfunction are often related to severe diseases. For examples of proteins localized to the mitochondria, see Figure 1.

Of all human proteins, 1070 (5%) have been experimentally shown to localize to the mitochondria in the Cell Atlas (Figure 2). A Gene Ontology (GO)-based analysis shows that biological processes related to cellular respiration are highly enriched among the mitochondrial proteins. Approximately 46% (n=493) of the mitochondrial proteome localizes to additional cellular compartments, most commonly to the nucleus or the cytosol. Analysis of the core mitochondrial proteins shows highly enriched terms for biological processes related to cellular respiration. More than half of the mitochondrial proteins localize to additional cellular compartments, most commonly to the cytoplasm or the nucleus.

The structure of the mitochondria

The mitochondrion, approximately 0.5-1 μm long, was first described in 1894 by Richard Altmann (Altmann R, 1890). It consists of an outer and inner membrane, with the intermembrane space in between. The folds of the inner membrane (denoted cristae) enclose the aqueous matrix, which contains the mitochondrial DNA (mtDNA) (Nunnari J et al, 2012). The mitochondrion is the only organelle in animals to possess a small genome of its own, consisting of 37 mitochondrial genes that are maternally inherited. Of these genes, 13 encode proteins in the respiratory chain, 22 encode transfer RNAs and 2 encode mitochondrial ribosomal RNAs (Friedman JR et al, 2014). The mtDNA is organized in a circular genome, which is packed into nucleoprotein complexes (nucleoids) (Jakobs S et al, 2014). Despite having their own genome, most of the proteins in the mitochondria are encoded by nuclear genes and imported into the mitochondria (Nunnari J et al, 2012). Although the mitochondrion has been known for more than a century, its proteome is still being explored, and proteins are continuously localized to its subcompartments (Rhee HW et al, 2013). For a curated list of protein markers for mitochondria, see Table 1. In Table 2, the 10 most highly expressed genes coding for mitochondrial proteins are summarized.

Table 1. Selection of proteins suitable as markers for the mitochondria or its substructures.

Table 2. Highly expressed single localizing mitochondrial proteins across different cell lines.

The mitochondria are continuously undergoing fission and fusion of individual mitochondrion in response to the cell's needs. Fusion of mitochondria allows for communication between individual mitochondrion, and possibly enables exchange of both mtDNA and its gene products. Loss of mitochondrial fission/fusion function is implicated with defects in oxidative phosphorylation, or loss of mtDNA (Friedman JR et al, 2014). The morphology of the mitochondria varies between different cell types, as shown in the examples of Figure 3.

The function of the mitochondria

The mitochondrial proteome is estimated to contain around 1000-1500 proteins, (Nunnari J et al, 2012; Friedman JR et al, 2014; Calvo SE et al, 2010) and has during the last decades been shown to participate in more cellular processes than previously believed. The mitochondria are well-known for their function of generating ATP through the electron transport chain and ATP synthase in the inner membrane, in a process known as oxidative phosphorylation. However, the mitochondria are also involved in several other cellular processes, including regulation of metabolism, calcium homeostasis and signaling (McBride HM et al, 2006). Importantly, the mitochondria also participate in cell cycle control, cell growth and differentiation, as well as play an important role in the induction of apoptosis. This is controlled by the release of cytochrome c from the intermembrane space, and it has been suggested that a trigger could be the binding of a proapoptotic protein to the mitochondria, leading to a caspase induced apoptosis (Green DR. 1998).

It has been estimated that the incidence of mitochondrial disorders may be 1 in 5000 individuals or higher, making it one of the most common inherited human diseases (Schaefer AM et al, 2004). The disorders can be caused by mutations in mitochondrial and/or nuclear DNA and phenotypically different diseases may stem from mutations in the same protein complexes (Nunnari J et al, 2012).

Gene Ontology (GO)-based analysis of the enriched genes in the mitochondrial proteome shows terms that are well in-line with the known functions of the mitochondria. The most highly enriched terms for biological processes are related to mitochondrial RNA metabolic processes, mitochondrial translation and cellular respiration (Figure 4a). Enrichment analysis of molecular function also shows significant enrichment for terms related to energy production, such as NADH dehydrogenase and oxidoreductase activity, as well as protein transmembrane transporter activity (Figure 4b).

Mitochondria proteins with multiple locations

Of the mitochondrial proteins detected in the Cell Atlas, 46% (n=493) also localize to other cellular compartments (Figure 5). The network plot shows that the most common locations shared with mitochondria are the cytosol, nucleoplasm and nucleoli, where nucleoplasm and nucleoli are overrepresented compared to the number of multilocalizing proteins in those compartments, and the cytosolic ones are underrepresented. These dual locations could highlight proteins functioning in e.g. DNA expression or regulation, protein synthesis and proteins imported into the mitochondria. Examples of mitochondrial proteins also localized to other cellular compartments are shown in Figure 6.

Expression levels of mitochondria proteins in tissue

The transcriptome analysis (Figure 7) shows that mitochondrial proteins are significantly more likely to be expressed in all tissue types compared of all genes with protein data in the Cell Atlas. This indicates that the mitochondria perform basic, essential functions, necessary for cell proliferation in all cells of the human body.

Relevant links and publications

Altmann R. 1890. Die Elementarorganismen Und Ihre Beziehungen Zu Den Zellen. Leipzig: Veit & comp., 145.

Calvo SE et al, 2010. The mitochondrial proteome and human disease. Annu Rev Genomics Hum Genet.
PubMed: 20690818 DOI: 10.1146/annurev-genom-082509-141720

Friedman JR et al, 2014. Mitochondrial form and function. Nature.
PubMed: 24429632 DOI: 10.1038/nature12985

Green DR. 1998. Apoptotic pathways: the roads to ruin. Cell.
PubMed: 9753316 

Jakobs S et al, 2014. Super-resolution microscopy of mitochondria. Curr Opin Chem Biol.
PubMed: 24769752 DOI: 10.1016/j.cbpa.2014.03.019

McBride HM et al, 2006. Mitochondria: more than just a powerhouse. Curr Biol.
PubMed: 16860735 DOI: 10.1016/j.cub.2006.06.054

Nunnari J et al, 2012. Mitochondria: in sickness and in health. Cell.
PubMed: 22424226 DOI: 10.1016/j.cell.2012.02.035

Rhee HW et al, 2013. Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science.
PubMed: 23371551 DOI: 10.1126/science.1230593

Schaefer AM et al, 2004. The epidemiology of mitochondrial disorders--past, present and future. Biochim Biophys Acta.
PubMed: 15576042 DOI: 10.1016/j.bbabio.2004.09.005