Mitochondria

Mitochondria generate the energy that is needed to power the functions of the cell, but also participate directly in several other cellular processes, including apoptosis, cell cycle control and calcium homeostasis. Mitochondria are distributed throughout the cytoplasm and vary in number between different cell types. Each organelle is enclosed by a double membrane, with the inner one forming the characteristic folds known as cristae. Mutations causing mitochondrial dysfunction are often related to severe diseases. Examples of proteins localized to mitochondria can be seen in Figure 1.

In the subcellular section, 1119 genes (6% of all protein-coding human genes) have been shown to encode proteins that localize to mitochondria (Figure 2). A Gene Ontology (GO)-based analysis shows that biological processes related to cellular respiration as well as to mitochondrial organization, gene expression and metabolic processes are highly enriched among the genes encoding mitochondrial proteins. Approximately 48% (n=539) of the mitochondrial proteome localizes to additional cellular compartments, most commonly to the nucleoplasm, nucleoli and/or the cytosol.

LRPPRC - U2OS
CHCHD3 - U2OS
CS - U2OS

PHB2 - U2OS
TRAP1 - U2OS
IMMT - U2OS

PCK2 - A-431
PYCR2 - U-251MG
PGAM5 - HEK293

Figure 1. Examples of proteins localized to the mitochondria. LRPPRC might play a role in transcription of mitochondrial genes (detected in U2OS cells). CHCHD3 is a protein in the MICOS complex, localized to the mitochondrial inner membrane (detected in U2OS cells). CS is active in the citric acid cycle (detected in U2OS cells). PHB2 is probably involved in the regulation of mitochondrial respiration activity (detected in U2OS cells). TRAP1 is important for maintaining mitochondrial function and polarization (detected in U2OS cells). IMMT is, just like CHCHD3, part of the MICOS complex located in the inner membrane (detected in U2OS cells). PCK2 catalyzes the conversion of oxaloacetate to phosphoenolpyruvate (detected in A-431 cells). PYCR2 catalyzes the last step in proline biosynthesis (detected in U-251 MG cells). PGAM5 may be a regulator of mitochondrial dynamics (detected in HEK 293 cells).

Figure 2. 6% of all human protein-coding genes encode proteins localized to the mitochondria. Each bar is clickable and gives a search result of proteins that belong to the selected category.

The structure of mitochondria

The mitochondrion was first described in 1890 by Richard Altmann. It is approximately 0.5-1 μm long and is enclosed by an outer and inner membrane seprated by an intermembrane space. The folds of the inner membrane, denoted cristae, enclose the aqueous matrix, which contains the mitochondrial DNA (mtDNA) and the majority of the mitochondrial proteins (Nunnari J et al. (2012)). The mitochondrion is the only organelle in animals to possess a small genome of its own, consisting of 37 genes in a circular genome of exclusively maternal inheritance. 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). However, the mitochondrial proteome has been estimated to contain around 1000-1500 proteins, and thus the great majority are encoded by nuclear genes and imported into mitochondria (Nunnari J et al. (2012); Nunnari J et al. (2012); Friedman JR et al. (2014); Calvo SE et al. (2010). Table 1 contains a list of proteins suitable as markers for mitochondria, while Table 2 contains highly expressed genes that encode mitochondrial proteins.

Table 1. Selection of proteins suitable as markers for mitochondria.

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

The number of mitochondria varies with cell type and according to the energy needs of individual cells. Mitochondria are continuously undergoing fission and fusion, which allows for regulation of the number of mitochondria as well as communication and exchange of mitochondrial components between individual mitochondria. Loss of mitochondrial fission/fusion function is associated with defects in oxidative phosphorylation and loss of mtDNA (Friedman JR et al. (2014)). The morphology and distribution of mitochondria varies between different cell types, as shown in the examples of Figure 3.

ALDH5A1 - CACO-2
NIPSNAP2 - SH-SY5Y
NDUFAF2 - MCF-7

PCK2 - Hep-G2
MAOA - RT-4
SDHA - HeLa

Figure 3. Examples of the morphology of mitochondria in different cell lines, represented by immunofluorescent staining of different mitochondrial proteins. ALDH5A1 in CACO-2 cells, NIPSNAP2 in SH-SY5Y cells and NDUFAF2 in MCF-7 cells. PCK2 in Hep-G2 cells, MAOA in RT-4 cells and SDHA in HeLa cells.

Figure 4. 3D-view of mitochondria in U2OS, visualized by immunofluorescent staining of CS. The morphology of mitochondria in human induced stem cells can be seen in the Allen Cell Explorer.

The function of mitochondria

Mitochondria are well-known for their function in generating ATP through the electron transport chain and ATP synthase, located in the inner membrane, in a process known as oxidative phosphorylation. However, mitochondria are also involved in several other cellular processes, including regulation of metabolism, calcium homeostasis and cell signaling (McBride HM et al. (2006)). They also have an important role in cell cycle control, cell growth, differentiation, and apoptosis.

The incidence of mitochondrial disorders has been estimated to 1 in 5000 individuals or higher, making it one of the most common types of heritable human diseases (Schaefer AM et al. (2004)). These 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 genes encoding proteins that localize to mitochondria shows enrichment of terms that are well in-line with the known functions of mitochondria. The most highly enriched terms for the GO domain Biological Process are related to transcription, translation and processing of proteins in mitochondria, structural organization of mitochondria, cellular respiration and metabolic processes (Figure 5a). Enrichment analysis of the GO domain Molecular Function also shows significant enrichment for terms related to energy production, such as NADH dehydrogenase and oxidoreductase activity, as well as transmembrane transporter activity (Figure 5b).

Figure 5a. Gene Ontology-based enrichment analysis for the mitochondria proteome showing the significantly enriched terms for the GO domain Biological Process. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Figure 5b. Gene Ontology-based enrichment analysis for the mitochondria proteome showing the significantly enriched terms for the GO domain Molecular Function. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Mitochondria proteins with multiple locations

Among the mitochondrial proteins detected in the subcellular section, 48% (n=539) also localize to other cellular compartments (Figure 6). The network plot shows that the most common locations shared with mitochondria are nucleoplasm, cytosol and nucleoli, with proteins localizing to mitochondria and nucleoplasm or nucleoli being overrepresented. Localization to both mitochondria and nucleus could highlight proteins functioning in gene expression, which occurs in both of these compartments. Examples of mitochondrial proteins also localizing to other cellular compartments are shown in Figure 7.

Figure 6. Interactive network plot of mitochondrial proteins with multiple localizations. The numbers in the connecting nodes show the proteins that are localized to the mitochondria and to one or more additional locations. Only connecting nodes containing more than one protein and at least 0.5% of proteins in the mitochondrial proteome are shown. The circle sizes are related to the number of proteins. The cyan colored nodes show combinations that are significantly overrepresented, while magenta colored nodes show combinations that are significantly underrepresented as compared to the probability of observing that combination based on the frequency of each annotation and a hypergeometric test (p≤0.05). Note that this calculation is only done for proteins with dual localizations. Each node is clickable and results in a list of all proteins that are found in the connected organelles.

CCDC51 - U2OS
FAM162A - U-251MG
COX7A2L - PC-3

Figure 7. Examples of multilocalizing proteins in the mitochondrial proteome. The examples show common or overrepresented combinations for multilocalizing proteins in the mitochondrial proteome. CCDC51 is an uncharacterized protein localized to both the nucleoplasm and mitochondria (detected in U2OS cells). FAM162A has been proposed to be involved in regulation of apoptosis (detected in U-251 MG cells). COX7A2L is an uncharacterized protein (detected in PC-3 cells).

Expression levels of mitochondria proteins in tissue

Transcriptome analysis and classification of genes into tissue distribution categories (Figure 8) shows that a larger portion of genes encoding mitochondrial proteins are detected in all tissues, while smaller portions are detected in some or many tissues, compared to all genes presented in the subcellular section. There is also a significantly smaller portion of the genes encoding proteins that localize to mitochondria that are not detected in any of the tissues that have been analyzed. This is in agreement with the roles of mitochondria in basic and essential functions in all cells of the human body.

Figure 8. Bar plot showing the percentage of genes in different tissue distribution categories for mitochondria-associated protein-coding genes, compared to all genes in the Subcellular Section. Asterisk marks a statistically significant deviation (p≤0.05) in the number of genes in a category based on a binomial statistical test. Each bar is clickable and gives a search result of proteins that belong to the selected category.

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