The wondrous mitochondrion and its proteome

The sequencing of human mitochondrial DNA, a circular DNA molecule contained in mitochondria, was completed in 1981, and, since then, roughly 150 mutations have been found that are associated with maternally inherited diseases (if you don't remember why mtDNA is inherited from the mother and not the father, check out this earlier post of mine). Despite this, the majority of human mitochondrial syndromes are actually caused by defects in the nuclear genome. This is sort of obvious if you think about it, given that human mitochondrial proteome consists of an estimated 1,100-1,400 distinct proteins, of which 13 are encoded by the mitochondrial DNA. The majority of proteins targeted at the mitochondria are actually encoded by nuclear genes. In fact

"The 13 proteins encoded by mammalian mtDNA are all components of the respiratory chain, which generates the majority of cellular ATP via oxidative phosphorylation (OXPHOS). However, the remaining respiratory chain subunits are encoded by nuclear genes, as are all proteins required for the transcription, translation, modification, and assembly of the 13 mtDNA proteins. All the components of numerous other mitochondrial pathways are also nuclear en- coded, including the tricarboxylic acid (TCA) cycle, protein import, fatty acid and amino acid oxidation, apoptosis, and biosynthesis of ketone bodies, pyrimidines, heme, and urea. Furthermore, during the decades following the sequencing of the mtDNA, it became clear that maternally inherited mitochondrial disorders represent only 20% of all inherited human mitochondrial disorders [1]."

Mitochondria are amazing organelles. Roughly half of mitochondrial proteins are ubiquitous and found across all organs, while the rest are tissue specific, meaning that their function and structure varies across cell lines. For example, when comparing mitochondria across different tissues, researchers found about a 75% overlap. In addition to this cell-type specificity, some of the mitochondrial proteins are expressed at very low levels or only during certain specific developmental stages, making the characterization of the mitochondrial proteome a challenging task. Today, a little over 1,000 of all mitochondrial proteins have been identified, mainly through large-scale proteomics, microscopy, and computation.

The first half of Calvo and Mootha's review [1] is an detailed report on the progress made so far in extensively classifying the mitochondrial proteome. They then proceed to discuss how the inventory of mitochondrial proteins has lead to the better understanding of mitochondrial disorders as well as the discovery of new disease genes.

"Traditionally, mitochondrial disease has referred primarily to disorders of oxidative ATP production, as discussed above. However the breadth of the mitochondrial proteome now implicates a large number of additional phenotypes, such as soft tissue tumors (paragangliomas) and diabetes mellitus. The discovery of new disease genes will further expand the clinical phenotypes associated with mitochondrial defects."

[1] Calvo, S., & Mootha, V. (2010). The Mitochondrial Proteome and Human Disease Annual Review of Genomics and Human Genetics, 11 (1), 25-44 DOI: 10.1146/annurev-genom-082509-141720